ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.

De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.

Musculoskeletal Symptoms Among Finnish Professional Orchestra Musicians.

BACKGROUND: The prevalence of musculoskeletal symptoms is high among professional musicians (73-88%). AIMS: We investigated the prevalence of musculoskeletal symptoms in Finnish symphony orchestra musicians. We compared individual instruments as well as the perceived demands of orchestral programs and difficulties in recovering after performances. METHODS: In this cross-sectional questionnaire 920 of 2,785 members of the Finnish Musicians' Union (33%) completed the questionnaire, including 361 full-time members of symphony orchestras. Questions about pain symptoms and frequency were based on the national survey done in 2011. RESULTS: Among the 361 full-time orchestra musicians, those playing all instruments experienced frequent pain, both in the last 30 days and exceeding 30 days in the last 12 months, in their neck or upper extremities. Female musicians experienced significantly more neck (69%), elbow (31%), and wrist (30%) pain than males (neck 52%, elbow 23%, wrist 19%). The profiles varied according to the different instruments and their playing positions. Musculoskeletal symptoms correlated with perceived demand of the orchestral program and difficulties in recovering after performances. Professional musicians experienced nearly twice as often neck pain in the last 30 days (female musicians 69%, male musicians 52%) than persons of the same age in the Finnish working population (female 41%, male 27%). CONCLUSION: Symphony orchestra musicians experience nearly twice as much musculoskeletal symptoms of the neck and upper extremities as others their age. To prevent musicians' playing-related problems, special emphasis should be focused on recovery after concerts, including the special demands of different composers and the frequency of rehearsals and performances.

Gut microbiota are related to Parkinson's disease and clinical phenotype.

In the course of Parkinson's disease (PD), the enteric nervous system (ENS) and parasympathetic nerves are amongst the structures earliest and most frequently affected by alpha-synuclein pathology. Accordingly, gastrointestinal dysfunction, in particular constipation, is an important non-motor symptom in PD and often precedes the onset of motor symptoms by years. Recent research has shown that intestinal microbiota interact with the autonomic and central nervous system via diverse pathways including the ENS and vagal nerve. The gut microbiome in PD has not been previously investigated. We compared the fecal microbiomes of 72 PD patients and 72 control subjects by pyrosequencing the V1-V3 regions of the bacterial 16S ribosomal RNA gene. Associations between clinical parameters and microbiota were analyzed using generalized linear models, taking into account potential confounders. On average, the abundance of Prevotellaceae in feces of PD patients was reduced by 77.6% as compared with controls. Relative abundance of Prevotellaceae of 6.5% or less had 86.1% sensitivity and 38.9% specificity for PD. A logistic regression classifier based on the abundance of four bacterial families and the severity of constipation identified PD patients with 66.7% sensitivity and 90.3% specificity. The relative abundance of Enterobacteriaceae was positively associated with the severity of postural instability and gait difficulty. These findings suggest that the intestinal microbiome is altered in PD and is related to motor phenotype. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and PD and the suitability of the microbiome as a biomarker.

[Nicotine and neurologic diseases--even a noxious substance may possess beneficial properties]. / Nikotiini ja neurologiset sairaudet--haitallisellakin aineella voi olla hyödyllisiä ominaisuuksia.

According to investigations, nicotine and its agonists may prevent the development of Parkinson's disease and reduce motor symptoms and dyskinesias in Parkinson's disease. It was shown recently that a transdermal nicotine patch reliefs the symptoms in patients suffering from mild cognitive impairment. In Alzheimer's disease an alpha7-selective agonist has been found to have positive effects on cognitive symptoms. Mutations of nicotinic receptors are underlying certain nocturnal frontal lobe epilepsies. The partial nicotine agonist varenicline may alleviate ataxia symptoms.

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily.

OBJECTIVES: To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC). METHODS: Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included Cmin, Cmax, Cmax - Cmin, AUC, t(1/2), and tmax. RESULTS: In healthy volunteers and PD patients, mean trough levels (Cmin), Cmax, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to Cmin, Cmax, and AUC, differences between the treatments in variability of levodopa concentrations (Cmax - Cmin) were less consistent. CONCLUSIONS: The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

SNCA mutation p.Ala53Glu is derived from a common founder in the Finnish population.

Mutations in SNCA are rare causes of familial Parkinson's disease (PD). We have previously described a novel p.Ala53Glu mutation in 2 Finnish families. To assess this mutation's frequency among Finnish PD patients, we screened 110 PD patients (mean age-of-onset 60 years) from Western Finland by Sanger sequencing of the third coding exon of SNCA. In addition, a sample of 47 PD subjects (mean age-of-onset 53 years) originating from Southern and Eastern Finland were studied using next-generation sequencing covering SNCA. Only one new individual with the p.Ala53Glu mutation was identified, confirming that this mutation is a rare cause of PD in the Finnish population. To search for a possible common origin of the p.Ala53Glu mutation, haplotype analysis was conducted in 2 families and in a patient from a third family (6 affected subjects) using both STR markers and a genome-wide SNP array. The results show that patients with the p.Ala53Glu mutation share a haplotype spanning a minimum of 5.7 Mb suggesting a common founder.

The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats.

It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinson's disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5 x 1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinson's disease.

Linking Smoking, Coffee, Urate, and Parkinson's Disease - A Role for Gut Microbiota?

While the etiology and pathogenesis of Parkinson's disease (PD) is still obscure, there is evidence for lifestyle factors influencing disease risk. Best established are the inverse associations with smoking and coffee consumption. In other contexts there is evidence that health effects of lifestyle factors may depend on gut microbiome composition. Considering the gastrointestinal involvement in PD, it was recently speculated, that the associations between smoking, coffee, and PD risk could be mediated by gut microbiota. Here we review such a possible mediatory role of gut microbiota taking into account recent findings on microbiome composition in PD and extending the scope also to urate.

Effects of an acute D2-dopaminergic blockade on the somatosensory cortical responses in healthy humans: evidence from evoked magnetic fields.

We tested the possible role of dopaminergic activity in the processing of somatosensory afferent information in healthy humans. Somatosensory evoked magnetic fields (SEFs) were recorded in seven subjects in response to left median nerve stimulation. SEFs were obtained in all subjects after oral administration of 2 mg haloperidol, an antagonist to dopaminergic D2 receptors, and placebo, which were given in a randomized, double-blind cross-over design. SEFs were analyzed using a multiple equivalent current dipole (ECD) model, with one dipole at the right primary somatosensory cortex (SI) and at both left and right secondary somatosensory cortices (SII). The earliest responses from SI, peaking at about 20 ms (N20m) and 35 ms (P35m), were not affected by haloperidol. A later deflection peaking at about 75 ms (P60m), however, was slightly reduced (p < 0.05). Responses arising from SII were not significantly changed. The results suggest that dopaminergic activity may be involved in modulating somatosensory processing after the initial stages of cortical activation.

Memory-based comparison process not attenuated by haloperidol: a combined MEG and EEG study.

Auditory P50 and N100 responses reflect preattentive processing, whereas subsequent mismatch negativity (MMN) response indexes memory-based comparison process. Divergent ERP responses have been found in schizophrenia and in Parkinson's disease (PD), which have abnormalities in cerebral dopamine activity. We used simultaneously magnetoencephalography and electroencephalography to investigate, whether a single dose of haloperidol, a dopamine D2-receptor antagonist, modulates preattentive auditory processing using a randomized, double-blind, placebo-controlled crossover design. Our results showed that haloperidol did not alter MMN to frequency and duration changes, whereas the magnetic MMN to frequency change was significantly accelerated. The amplitude and latency changes of the electric and magnetic P50 and N100 were insignificant. Our results indicate that memory-based sound comparison and preceding cortical processing underlying stimulus detection are not attenuated by haloperidol, whereas haloperidol appears to accelerate preattentive sound comparison.

Effects of scopolamine on MEG spectral power and coherence in elderly subjects.

OBJECTIVE: Scopolamine, a muscarinic receptor antagonist, can produce temporary cognitive impairments as well as electroencephalographic changes that partially resemble those observed in Alzheimer's disease. In order to test the sensitivity of spectral power and hemispheric coherence to changes in cholinergic transmission, we evaluated quantitative magnetoencephalogram (MEG) after intravenous injection of scopolamine. METHODS: MEG of 8 elderly healthy subjects (59-80 years) were measured with a whole-head magnetometer after intravenous injection of scopolamine. An injection of glycopyrrolate, a peripheral muscarinic antagonist, was used as the placebo in a double-blind, randomized, cross-over design. Spectral power and coherence were computed over 7 brain regions in 3 frequency bands. RESULTS: Scopolamine administration increased theta activity (4-8 Hz) and resulted in the abnormal pattern of MEG desynchronization in eyes-open vs. eyes-closed conditions in the alpha band (8-13 Hz). These effects were most prominent over the posterior regions. Interhemispheric and left intrahemispheric coherence was significantly decreased in the theta band (4-8 Hz). CONCLUSIONS: Spontaneous cortical activity at the theta and alpha range and functional coupling in the theta band are modulated by the cholinergic system. MEG may provide a tool for monitoring brain dynamics in neurological disorders associated with cholinergic abnormalities.

Dopamine modulates involuntary attention shifting and reorienting: an electromagnetic study.

OBJECTIVE: Dopaminergic function has been closely associated with attentional performance, but its precise role has remained elusive. METHODS: Electrophysiological and behavioral methods were used to assess the effects of dopamine D2-receptor antagonist haloperidol on involuntary attention shifting using a randomized, double-blind, placebo-controlled cross-over design. Eleven subjects were instructed to discriminate equiprobable 200 and 400ms tones in a forced-choice reaction-time (RT) task during simultaneous measurement of whole-head magnetoencephalography and high-resolution electroencephalography. RESULTS: Occasional changes in task-irrelevant tone frequency (10% increase or decrease) caused marked distraction on behavioral performance, as shown by significant RT increases to deviant stimuli and subsequent standard tones. Furthermore, while the standard tones elicited distinct P1-N1-P2-N2-P3 waveforms, deviant tones elicited additional mismatch negativity (MMN), P3a, and reorienting negativity (RON) responses, indexing brain events associated with involuntary attention shifting. While haloperidol did not affect the source loci of the responses of magnetic N1 and MMN, the amplitude of the electric P3a and that of RON were significantly reduced and the latency of magnetic RON were delayed following haloperidol administration. CONCLUSIONS: The present results suggest that dopamine modulates involuntary attention shifting to task-irrelevant deviant events. It appears that dopamine may disrupt the subsequent re-orienting efforts to the relevant task after distraction.

Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology.

We describe the clinical, neuropathological, and genetic features of a Finnish patient with a novel α-synuclein (SNCA) mutation A53E. The patient was clinically diagnosed with atypical Parkinson's disease (PD) with age of onset at 36 years. In the neuropathological analysis performed at the age of 60 years, highly abundant SNCA pathology was observed throughout the brain and spinal cord showing features of multiple system atrophy and PD. Neuronal and glial (including oligodendroglial) SNCA inclusions and neurites were found to be particularly prominent in the putamen, caudatus, amygdala, temporal and insular cortices, gyrus cinguli, and hippocampus CA2-3 region. These areas as well as the substantia nigra and locus coeruleus showed neuronal loss and gliosis. We also found TDP-43 positive but mostly SNCA negative perinuclear inclusions in the dentate fascia of the hippocampus. The A53E mutation was found in 2 other relatives who had parkinsonism. Our results suggest that the novel SNCA A53E substitution is a causative mutation resulting clinically in parkinsonism and pathologically in severe multiple system atrophy- and PD-type phenotype.

Problems with the present inhibitors and a relevance of new and improved COMT inhibitors in Parkinson's disease.

Entacapone and tolcapone are reversible COMT inhibitors which have been approved for clinical use in patients with Parkinson disease (PD). Nebicapone is a third COMT inhibitor which has been studied in humans. COMT inhibitors are used in combination with levodopa and a dopa decarboxylase (DDC) inhibitor. Each of them has problems either in pharmacokinetics, pharmacodynamics, clinical efficacy, or in safety. All three inhibitors have short elimination half-lives, about 2-3h. Tolcapone is longer acting and more potent COMT inhibitor than entacapone; nebicapone lies in between. However, none of the present inhibitors cause a complete peripheral COMT inhibition. Tolcapone and nebicapone have increased more levodopa AUC than entacapone which is reflected also in their clinical efficacy. The most common adverse event with COMT inhibitors is dyskinesia which is usually managed by decreasing levodopa dose. The greatest problem with tolcapone and probably also with nebicapone is their liver toxicity which is not seen with entacapone. Tolcapone causes severe diarrhea more often than entacapone. Though the present COMT inhibitors have improved significantly the treatment of advanced PD patients, they still have several problems and weaknesses leaving room for developing better COMT inhibitors.

Cholinergic modulation of preattentive auditory processing in aging.

Auditory event-related potential (ERP) components P50 and N100 are thought to index preattentive auditory processing underlying stimulus detection, whereas a subsequent component termed mismatch negativity (MMN) has been proposed to reflect comparison of incoming stimuli to a short-lived sensory memory trace of preceding sounds. Existing evidence suggests impairment of preattentive auditory processing in aging, which appears to be accompanied by decline of cholinergic activity. Previous studies indicate that scopolamine, which is a centrally acting muscarinic receptor antagonist, modulates preattentive auditory processing in young subjects. It has remained elusive, however, to which extent scopolamine affects preattentive auditory processing in aged subjects. We measured auditory responses simultaneously with electroencephalogram (EEG) and magnetoencephalogram (MEG) from nine non-demented elderly subjects after intravenous injection of scopolamine or glycopyrrolate, the latter being a peripherally acting cholinergic antagonist, using a double blind protocol. Scopolamine significantly delayed electric P50, both electric and magnetic N100 responses, whereas subsequent MMN and P200 responses were not altered by scopolamine. Our results indicate that the cholinergic system modulates auditory processing underlying stimulus detection in aging. In addition, auditory evoked responses appear to have different age-related sensitivity to cholinergic modulation. The combined MEG/EEG measurements using particularly auditory N100 response might offer an objective tool to monitor cholinergic activity in aging and Alzheimer's disease (AD).