Decreased Coenzyme Q10 Levels in Multiple System Atrophy Cerebellum.

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Cognitive impairments associated with morphological changes in cortical and subcortical structures in multiple system atrophy of the cerebellar type.

BACKGROUND AND PURPOSE: Patients with the cerebellar variant of multiple system atrophy (MSA-C) often show cognitive deficits in various cognitive domains. The association between morphometric changes in cortical and subcortical structures and cognitive impairments in MSA-C were investigated to explore the neural correlates responsible for cognitive deficits in MSA-C patients. METHODS: Using surface-based morphometry, region-of-interest cortical thickness and the volumes and shapes of subcortical structures were examined in 18 patients who fulfilled the criteria of probable MSA-C and were compared to 50 healthy controls. The association between regional changes and cognitive functions in MSA-C were investigated by applying linear regression analyses after controlling for confounding factors. RESULTS: Compared with controls, the patients with MSA-C showed significant cortical thinning in the fronto-temporo-parietal regions and volume reduction in subcortical structures with shape changes. Cerebellar volume had no significant effect on cortical and subcortical volumes. The severity of atrophic changes in the bilateral thalamus, the left cerebellum and the left pericalcarine gyrus were significantly correlated with attentional, executive and visuospatial dysfunctions. CONCLUSION: Cognitive impairment in MSA-C might result from functional disruption of the corticostriatal and pontocerebellar circuit mediated by primary cortical, cerebellar or thalamic pathology.

Último minuto en atrofia multisistémica / Latest update on multiple system atrophy

Introducción. La Atrofia Multisistémica (AMS) es un trastorno neurodegenerativo, rápidamente progresivo, esporádico, que se presenta con una combinación de síntomas disautonómicos, parkinsonianos, cerebelosos, y corticospinales. La etiopatogenia es desconocida, pero parece existir un papel genético subyacente que implica a la α-sinucleína. El diagnóstico temprano de la enfermedad ha mejorado con los nuevos criterios clínicos de 2008, apoyados por técnicas de neuroimagen estructural y funcional. El tratamiento sigue siendo sintomático, pero se han publicado recientes ensayos clínicos con opciones terapéuticas que intentan frenar la progresión natural de la enfermedad. Objetivo. Revisar los avances más notorios publicados en la literatura científica en los últimos 5 años en la AMS. Desarrollo. Se ha revisado la literatura de los últimos años y se presentan los avances más significativos en la patogenia, diagnóstico, y tratamiento de la AMS, así como las principales perspectivas futuras en dichos campos. Conclusiones. La patogenia de la AMS sigue siendo desconocida, aunque las variaciones en el locus SNCA del cromosoma 4q22.1 que codifica la α-sinucleína juegan un papel destacado. Los nuevos criterios diagnósticos han permitido mejorar la precisión diagnóstica en los estadios iniciales de la enfermedad. Existen diversos ensayos clínicos con prometedoras terapias modificadoras de la enfermedad, aunque son necesarios más estudios futuros para determinar el verdadero alcance clínico de las mismas (AU)

Introduction. Multiple System Atrophy (MSA) is a neurodegenerative, quickly progressive, sporadic disorder that presents with a combination of dysautonomic, parkinsonian, cerebellar and corticospinal symptoms. The aetiopathogenesis is unknown, but there seems to be an underlying genetic role involving a-synuclein. Early diagnosis of the disease has improved with the new clinical criteria of 2008, backed by structural and functional neuroimaging techniques. Treatment continues to be symptomatic, but recent clinical trails have been conducted with therapeutic options that attempt to curb the natural progression of the disease. www.neurologia.com Rev Neurol 2012; 54 (Supl 4): S45-S51 S51 PONENCIA Aims. The purpose of this study is to review the most significant advances in MSA reported in the scientific literature in the last 5 years. Development. The literature from the last few years was reviewed and we report on the most significant advances in the pathogenesis, diagnosis and treatment of MSA, as well as the main future perspectives in those fields. Conclusions. The pathogenesis of MSA remains unknown, although variations in the SNCA locus of chromosome 4q22.1, which codes for a synuclein, play an important role. The new diagnostic criteria have allowed diagnosis to become more accurate in the early stages of the disease. Several clinical trials have been carried out with promising disease-modifying therapies, although further studies will be needed in the future to determine their true clinical scope (AU)

[Neuro-urological dysfunction of the lower urinary tract in CNS diseases: pathophysiology, epidemiology, and treatment options]. / Neurourologische Funktionsstörungen des unteren Harntraktes bei Erkrankungen des ZNS : Pathophysiologie, Epidemiologie und Therapieoptionen.

The lower urinary tract (LUT) is regulated by a complex neural network that is subject to supraspinal control. Neurological disorders, especially of the central nervous system (CNS), can rapidly lead to disruption of this control. Multiple sclerosis, Parkinson's disease, multiple system atrophy, and stroke are neurological disorders which quite frequently cause dysfunction of the LUT. With respect to the pathophysiology of bladder dysfunction in CNS diseases there are various hypotheses regarding the individual disorders: disturbances of neural communication between the frontal cortex and pontine micturition center, between the pontine micturition center and the lumbosacral parts of the spinal cord, and between the basal ganglia, thalamus, and anterior cingulate gyrus appear to play a pivotal role in the development of bladder dysfunction. The symptoms and urodynamic presentation of LUT dysfunction can vary considerably depending on the disease and disease progression and can change in the course of the disease. The incidence and prevalence of LUT dysfunctions rise with increasing progression of the underlying neurological disease.Various conservative, minimally invasive, and open surgical procedures are available to prevent harmful sequelae and to improve the quality of life of these patients. As yet, however, few data exist on most of the treatment options in cases of the above-mentioned CNS diseases. Intermittent self-catheterization and antimuscarinic medications are among the most important conservative treatment options. Injection of botulinum neurotoxin type A into the detrusor muscle and increasingly sacral or pudendal neuromodulation are among the most important minimally invasive treatment options. Surgical methods include reconstructive continent or incontinent urinary diversion.When planning therapy the patient's current needs and neurological limitations as well as possible disease progression must be taken into consideration. It is often advisable to consult with and enlist the cooperation of the attending neurologist when planning treatment.

Functional mapping in PD and PSP for sustained phonation and phoneme tasks.

AIM: To elucidate the central basis of articulatory speech disorders in Parkinsonian syndromes using functional magnetic resonance imaging (fMRI). METHODS: Twenty-two patients with Parkinson's disease (PD) and 18 with progressive supranuclear palsy (PSP) were clinically evaluated for speech dysfunction. Functional magnetic resonance imaging (fMRI) was carried out in these patients using sustained phonation and phoneme tasks. Individual and group analysis using SPM2 was done for eight patients with PD, 7 with PSP and 6 healthy controls. SETTING: Tertiary Medical Teaching Institute. RESULTS: For sustained phonation paradigm, superior temporal gyrus area was activated in PD patients, and occipital cortex in PSP subjects in comparison to controls. For phoneme paradigm, the patients with PD recruit lingual gyrus obviating the need for more efforts for the task. Also wider areas as well as more clusters were activated in PD patients compared to controls. Lingual gyrus was found to be strongly activated in PSP patients. Reduced activation of the primary areas with recruitment of remote areas was another prominent finding in PSP. Due to excessive motion (>1.5 mm, >1 degrees ) in all the MSA patients, they could not be considered for analysis. CONCLUSION: The failure of the executive fronto-striatal network would lead to increased activation of other areas in PD, but in PSP, there is a widespread cortical dysfunction.

Longitudinal study of bone and calcium metabolism and fracture incidence in spinocerebellar degeneration.

Little is known about bone and calcium metabolism and fracture incidence in spinocerebellar degeneration (SCD) despite frequent falls and immobilization. To address bone and calcium metabolism and fracture incidence in SCD, we conducted a 10-year prospective study in a cohort of adult patients with SCD. Bone mineral density (BMD) and serum levels of ionized calcium, parathyroid hormone, 25-hydroxyvitamin D, and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) were followed in 110 patients with SCD for 10 years. Age-matched healthy volunteers (n = 110) served as controls. At baseline, the SCD patients had a low BMD with high levels of serum ionized calcium and ICTP which correlated with the degree of immobilization (Barthel index). Over 10 years, serum 25-hydroxyvitamin D decreased to the osteomalacic level (<5 ng/ml), and calcium and ICTP further increased in accordance with a decreased Barthel index score. The BMD decreased by 15.2% in men and by 24.6% in women. The incidence of fractures in the patients was significantly higher as compared with the control group (men 8/49 vs. 1/42, p = 0.0428; women 16/49 vs. 2/48, p = 0.0026). Over 10 years, the BMD was significantly reduced in the SCD patients, particularly in women, which increased the risk of a fracture. Vitamin D deficiency due to sunlight deprivation, increased bone resorption due to immobilization, and frequent falls are probable causes of osteoporosis and fractures in these patients. Hypovitaminosis D and increased bone resorption may be corrected readily by the routine use of vitamin D supplements together with bisphosphonate.

Parkinson's disease-like presentation of multiple system atrophy with poor response to STN stimulation: a clinicopathological case report.

We report on a clinicopathological case of multiple system atrophy with good response to levodopa and subsequent development of motor complications. Because the subject complied with all the inclusion criteria (Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease), bilateral subthalamic nucleus deep brain stimulation electrodes were implanted.

Motor cortical stimulation for parkinsonism in multiple system atrophy.

BACKGROUND: Functional neuroimaging studies have demonstrated disturbances in the activity of premotor and motor cortices in Parkinson disease and in animal models of parkinsonism that improve in response to effective basal ganglia surgical therapy. Techniques that directly alter the function of these cortical areas, such as transcranial magnetic stimulation, have been applied in patients with Parkinson disease, with transient improvement in their bradykinesia and gait dysfunction. Recently, a patient with refractory Parkinson disease was claimed to have obtained a marked bilateral clinical benefit from extradural unilateral motor cortical stimulation. We hypothesized that direct cortical stimulation could alleviate the disability of the treatment-refractory parkinsonian symptoms commonly present in MSA. OBJECTIVE: To evaluate the efficacy of motor cortical stimulation in patients with refractory parkinsonism due to multiple system atrophy (MSA). METHODS: Five patients with a diagnosis of MSA with predominant parkinsonism underwent surgery for subdural motor cortical stimulation. MAIN OUTCOME MEASURES: Changes in activities of daily living and motor subscores on the Unified Parkinson's Disease Rating Scale 12 hours after medication withdrawal. Scores at baseline and 3 to 6 months following surgery were compared. RESULTS: All patients had a decline in motor scores at the follow-up evaluations despite the application of a variety of adjustments. The activities of daily living score mildly worsened by 9.7% (95% confidence interval, 32.3 to-13.0; P =.37) and the motor score worsened by 25.6% (95% confidence interval, 58.7 to -7.5; P =.06). Despite objective worsening over time and no deterioration when stimulation was immediately turned off, 3 patients still claimed subjective benefit and requested continued stimulation. No patients suffered adverse effects from the surgery or long-term stimulation, although 1 patient had a stimulation-induced seizure during the initial programming. The range of settings for 4 patients with bipolar configuration and 1 patient with monopolar configuration were as follows: amplitude, 3 to 3.6 V; pulse width, 40 to 90 milliseconds; and pulse rate, 145 to 185 Hz. CONCLUSIONS: Our data suggest that motor cortical stimulation using these parameters fails to improve the motor disability in MSA. Worsening of motor scores was likely a function of disease progression.

REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA.

OBJECTIVE: To explore the neurochemical basis of REM sleep behavior disorder (RBD) in multiple-system atrophy (MSA). METHODS: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of REM atonia loss by the percentage of REM sleep with tonically increased electromyographic (EMG) activity and the percentage of REM sleep with phasic EMG bursts. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was employed to measure the density of striatal monoaminergic terminals and SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) to measure the density of 123I]IBVM. RESULTS: Age and gender distributions were similar in patient and normal control groups. The MSA subjects showed decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) and decreased [123I]IBVM binding in the thalamus (p < 0.001). Moreover, in the MSA group, striatal [11C]DTBZ binding was inversely correlated with the severity of REM atonia loss (p = 0.003). Thalamic [123I]IBVM binding, however, was not correlated to the severity of REM atonia loss. CONCLUSION: Decreased nigrostriatal dopaminergic projections may contribute to RBD in MSA.

Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA.

OBJECTIVE: To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA). METHODS: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea-hypopnea index during sleep. SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [123I]IBVM and 15 normal control subjects utilizing [11C]DTBZ. RESULTS: Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [123I]IBVM binding in the thalamus (p < 0.001) and decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) in comparison with the control subjects. In the MSA group, thalamic [123I]IBVM binding was inversely correlated with the severity of OSA (p = 0.011). Striatal [11C]DTBZ binding was not correlated with the severity of OSA (p = 0.19). CONCLUSION: Decreased pontine cholinergic projections may contribute to OSA in MSA.

Attention and cognition in bradykinetic-rigid syndromes: an event-related potential study.

Bradykinetic-rigid syndromes are often accompanied by cognitive impairment. Because prominent motor involvement in these disorders may interfere with neuropsychological testing, we used event-related potentials (ERPs) for the assessment of cognition and attention in 41 patients with various bradykinetic-rigid syndromes of less than 5 years duration: idiopathic Parkinson's disease corticobasal degeneration, Steele-Richardson-Olszewski syndrome (SRO), and multiple system atrophy. Patients were compared with matched normals. ERP abnormalities in the auditory "oddball" paradigm were found only in corticobasal degeneration and SRO. ERP abnormalities in selective attention tasks were present in all patient groups, changes in SRO being the most prevalent. Abnormalities in corticobasal degeneration were present under "less-attention-demanding" conditions and suggested involvement of posterior parts of the brain. Multiple system atrophy and idiopathic Parkinson's disease patient groups had minimal ERP abnormalities. However, reaction times in MSA were longer in all paradigms. The results of the study support the view that bradykinetic-rigid syndromes involve some attentional deficits, but also have distinct reaction time and ERP characteristics, which may be helpful in differential diagnosis.

Phosphorus magnetic resonance spectroscopy in multiple system atrophy and Parkinson's disease.

We performed in vivo phosphorus magnetic resonance spectroscopy on the occipital lobes of 15 patients with multiple system atrophy (MSA; eight with olivopontocerebellar atrophy [OPCA] and seven with the striatonigral degeneration variant [SND]), 13 patients with idiopathic Parkinson's disease (PD), and 16 age-matched healthy subjects. The MSA group showed significantly reduced phosphocreatine (PCr), increased inorganic phosphate (Pi), and unchanged cytosolic free [Mg2+], and pH. We did not find any significant difference between the OPCA and SND variants. However, patients with PD showed significantly increased content of Pi, decreased cytosolic free [Mg2+], and unchanged [PCr] and pH. Comparing the MSA and PD groups, [PCr] was significantly lower in MSA than in PD, whereas cytosolic free [Mg2+] was significantly lower in PD. Despite a certain degree of overlap of [PCr] and [Mg2+] values between the two groups, by considering both variables at the same time it was possible to classify correctly 93% of cases by discriminant analysis. We conclude that phosphorus magnetic resonance spectroscopy discloses abnormal phosphate metabolite and ion contents in both MSA and PD, respectively, and may provide noninvasive diagnostic help to differentiate MSA from PD.