Feasibility of a randomized, sham-controlled pilot study for accelerated rTMS-treatment of the cerebellum plus physiotherapy in CANVAS patients.

BACKGROUND: Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. OBJECTIVE: To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. METHODS: Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. RESULTS: All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. CONCLUSION: The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.

Effects of cerebellar repetitive transcranial magnetic stimulation plus physiotherapy in spinocerebellar ataxias - A randomized clinical trial.

BACKGROUND: In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are urgently needed. Transcranial magnetic stimulation is a promising therapeutic option, but applicability is limited by lengthy duration of stimulation protocols. METHODS: In this randomized sham controlled clinical trial, patients were assigned to verum (n = 15) or sham (n = 18) cerebellar transcranial magnetic stimulation. To yield best possible treatment effects, both intervention groups received intensified physiotherapy for the duration of the study. RESULTS: Ataxia severity was reduced by 1.6 points on the Scale for assessment and Rating of Ataxia among patients in the verum group (p < 0.001). Clinical improvement was significantly larger in the verum group, compared to the sham group (p < 0.01). The treatment effect was mainly carried by improved appendicular coordination. Patients in the verum group also significantly improved in the 8 Meter Walk Test (p < 0.05) and PATA rate (p < 0.01). CONCLUSIONS: Cerebellar rTMS ameliorates ataxia severity in patient with spinocerebellar ataxia. Condensing treatment duration to only 5 days without reduction of treatment effects facilitates applicability and therefore broadens availability to larger patient populations.

RTMS of the Cerebellum Using an Accelerated Stimulation Protocol Improved Gait in Parkinson's Disease.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological and noninvasive brain stimulation technique that has been proven to be effective in Parkinson's disease (PD). The combination of rTMS and treadmill training improved gait function in PD greater than treadmill training alone. OBJECTIVE: The aim of our study was to evaluate the combination of a novel high-intensity, short intervention rTMS treatment and a multimodal treatment protocol including of physiotherapy, occupational therapy and language therapy, the so-called Parkinson's Disease Multimodal Complex Treatment (PD-MCT), to improve motor function. METHODS: In this randomized double-blind sham-controlled trial rTMS with 48 Hz or sham was applied over the cerebellum 3 times a day for 5 consecutive days. Patients were assessed at baseline (V0), after 5 days of treatment (V1), and 4 weeks later (V2). The primary clinical outcome measure was the motor sum-score of the Unified PD Rating Scale (UPDRSIII), secondary clinical outcomes were quantitative motor tasks. RESULTS: A total of 36 PD patients were randomly allocated either to rTMS (n = 20) or sham (n = 16), both combined with PD-MCT. rTMS improved the UDPRSIII score comparing baseline and V1 in the treatment group by -8.2 points (P = .004). The 8MW and dynamic posturography remained unchanged in both groups after intervention. Conclusion. Compressing weeks of canonical rTMS protocols into 5 days was effective and well tolerated. rTMS may serve as an add-on therapy for augmenting the multimodal complex treatment of motor symptoms, but seems to be ineffective to treat postural instability.

Isolated slow orthostatic tremor of the trunk.

Slow orthostatic tremor is an extremely rare movement disorder with relatively low-frequency tremor (< 13 Hz) in the legs and trunk, which is evoked by standing. There is still much controversy regarding its precise etiology. Here we present a 57 year-old female patient with a slow orthostatic tremor variant who experienced progressive gait disturbances since six years due to isolated trunk tremor. Potential symptomatic causes of tremor and other neurological co-morbidities were excluded through an exenstive clinical, laboratoy and imaging work-up. Subsequently, a combined treatment with propranolol and primidone was started, which resulted in almost complete resolution of the trunk tremor. Given that the slow trunk tremor in this patient almost completely resolved after therapy with a low-dose propranolol and primidone, considered first line drugs for the treatment of essential tremor, this case illustrates that isolated orthostatic trunk tremor may occur as a rare variant of essential tremor.

Epigenome-Wide Analysis of DNA Methylation in Parkinson's Disease Cortex.

Background: Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene−environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson's disease, which that is characterised by a late onset in life. Aims: To determine epigenetic modifications in the brains of Parkinson's disease patients. Patients and Methods: DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels of CYP2E1 were analysed using Western blot in human cortex and knock-out mice brain samples. Results: We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference >0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation of CYP2E1 was unchanged. In CYP2E1 knock-out mice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulated CYP2E1 protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes. Conclusions: Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation of CYP2E1.

Safety of Cerebrolysin for Neurorecovery after Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Twelve Randomized-Controlled Trials.

We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis were conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p > 0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo.

Sudden paraparesis due to spinal cord ischemia with initial contrast enhancement of the cauda equina and time-delayed owl-eyes sign on follow-up MR imaging: a case report.

We report on a case of a 52-year-old male with sudden paraparesis. The initial MRI showed contrast enhancement of the conus medullaris and the complete cauda equina. Follow-up MRI revealed a spinal ischemia in the anterior portion of the spinal cord. Only a few reports with similar findings have been published. We suggest that contrast enhancement of the conus medullaris and descending nerve roots can be a potential first indicator of a spinal cord ischemia.

Remarkable improvement of primary orthostatic tremor using perampanel.

Management of primary orthostatic tremor (POT) remains challenging, and medication is often ineffective. We report the case of a 53-year-old female with orthostatic tremor for 6 years who was refractory to gabapentin, clonazepam, primidone and propranolol. After treatment with 4 mg/day perampanel, she reported almost complete resolution of tremor. The diagnosis of POT was confirmed by tremor analysis using surface electromyography. Our report shows the potential use of the novel AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist perampanel for the treatment of POT. To date, only two similar patients, one refractory to treatment and the other previously treated with clonazepam only, have been reported. We would like to note that our patient was refractory to all previous therapy and responded to a low dose of perampanel without side effects. The striking clinical improvement suggests a putative role of glutamate in the pathophysiology of orthostatic tremor.

Effects of Rivastigmine on Patients with Spinocerebellar Ataxia Type 3: A Case Series of Five Patients.

BACKGROUND: Rivastigmine is an acetylcholine esterase inhibitor which is commonly used as therapy for dementia in Alzheimer's disease and Parkinson's disease (PD). Recently, a randomized controlled trial demonstrated a positive effect of rivastigmine on gait function in nondemented PD patients. Disturbed gait is a shared hallmark of PD and ataxias. OBJECTIVES: We hypothesized that the effect of rivastigmine could be translated to spinocerebellar ataxia (SCA) improving gait function. METHOD: Five patients with SCA type 3 were treated with transdermal rivastigmine for 8 weeks. The patients were monitored using the Scale for the Assessment and Rating of Ataxia (SARA) and an electronic walkway system (GAITRite®). RESULTS: Gait function was not changed by treatment, but 4 patients who continued treatment for 8 weeks showed improved coordination of extremities. The SARA sum score, which was 7.6 ± 2.2 at baseline, had dropped by 1.5 ± 1.9 after 4 weeks and by 2.1 ± 1.4 after 8 weeks. CONCLUSIONS: Contrary to our hypothesis, we observed no improvement of gait parameters as assessed by SARA and GAIT-Rite®, but coordination abilities were improved. Rivastigmine was well tolerated, but known side effects of rivastigmine, such as deterioration of asthma, may appear. Further trials in larger cohorts are needed to confirm our findings.

[Successful Systemic Lysis Therapy in Acute Retinal Arterial Occlusions]. / Erfolgreiche systemische Lysetherapie bei akuten retinalen Arterienverschlüssen.

BACKGROUND: Retinal artery occlusion leads to dramatic and irreversible vision loss. There is currently no evidence-based standard therapy. According to the German guidelines on retinal artery occlusions, intravenous fibrinolysis therapy can be performed up to a time window of 4 h 30 min. METHODS: Two patients were treated accordingly. RESULTS: In patient 1, systemic lysis therapy was used in branch retinal artery occlusion (BRAO) of the inferior temporal retinal artery with macular involvement 4 h 15 min after symptom onset. Immediately after the therapy, the patient reported significant improvement in symptoms. Three months after therapy, retinal function was good, but with subtle atrophy of the inner neurosensory retina. Patient 2, 2 h 30 min after onset of symptoms of the inferior temporal BRAO, the patient experienced further deterioration, with clinical signs of a central retinal artery occlusion (CRAO). Visual acuity deteriorated to light perception. Emergency intravenous lysis therapy, administered 3 h later, gave an improvement in visual acuity with preservation of the inferior visual field. In both patients, a marked improvement in visual acuity was observed immediately after the lysis therapy: Patient 1: right eye, best corrected visual acuity (BCVA) initial 0.5, BCVA 3 days after lysis therapy 1.0, no defects in Goldmann visual field. Patient 2: left eye, BCVA initial 0.4, then sudden deterioration to light perception, BCVA 1 month after lysis therapy 0.6, persisting visual field defects in the superior hemisphere with preservation of the inferior visual field. CONCLUSIONS: Two patients with acute retinal artery occlusion were treated successfully with systemic intravenous fibrinolysis.

Resting-state fMRI reveals increased functional connectivity in the cerebellum but decreased functional connectivity of the caudate nucleus in Parkinson's disease.

Objective: Frequent falls are common in Parkinson's disease (PD). Resting-state fMRI (rs-fMRI) studies have found differences in functional connectivity between PD patients and healthy controls. However, whether functional connectivity in PD patients with frequent falls (PD-fallers) differs from those without falls (PD-non fallers) is unknown. Therefore, to elucidate the underlying mechanisms leading to postural instability in PD patients with frequent falls, we compared changes in functional connectivity between PD-fallers, PD-non fallers and healthy controls.Methods: Thirteen healthy controls (70.7 ± 7.2 years) were compared to thirteen PD-fallers (70.6 ± 5.9 years) and 19 PD-non fallers (71.61 ± 5.8 years) without cognitive impairment. We performed 1.5T rs-fMRI scans and evaluated gait and balance, motor symptoms and cognitive functions.Results: Cerebellar seed regions showed increased functional connectivity in PD-fallers compared to controls in two connections between the cerebellar cortex and vermis (p-value = 0.02). Conversely, in comparison to controls, functional connectivity between the precuneus and caudate nucleus was decreased in PD-non fallers (p-value = 0.015). A similar trend was also observed between controls and PD-fallers, although this difference did not reach statistical significance.Discussion: We found increased functional connectivity among cerebellar structures in PD, which may reflect an adaptive (compensatory) mechanism through activation of additional brain structures to restore gait function. In contrast, a relative disconnection between the precuneus and caudate nucleus in PD patients might indicate an impaired brain network unrelated to the risk of falls. Cerebellar areas might thus be considered as future therapeutic targets for neuromodulatory treatment of postural instability in PD.Abbreviations: DMN: default mode network; FC: functional connectivity; IPL: inferior parietal lobule; MMSE: Minimal Mental Status Examination; PD: Parkinson's disease; rs-fMRI: resting-state functional Magnetic Resonance Imaging; UPDRSIII: Unified Parkinson's disease ranking scale.

Transcutaneous vagal nerve stimulation improves gastroenteric complaints in Parkinson's disease patients.

BACKGROUND: Gastrointestinal dysfunctions are common in Parkinson's disease. Their management is still challenging and new treatment options are needed. OBJECTIVE: To test whether transcutaneous vagal nerve stimulation can improve gastrointestinal dysfunction in patients with Parkinson's disease. METHODS: We performed a randomized double-blind pilot study enrolling patients suffering from Parkinson's disease with gastroenteric complaints. Patients were randomized to use either a sham-device or to stimulate the vagal nerve with an electric device over the course of four weeks with four stimulations per day. Ten patients (aged 69.6±4.6 years) were randomized for the intervention group, and nine patients (aged 67.2±6.3 years) used a sham-device. Clinical outcome was evaluated using the Gastrointestinal Symptom Rating Scale whereas gastrointestinal motility was measured with the 13C-octanoic acid breath test. RESULTS: In the treatment group, vagal nerve stimulation improved the Gastrointestinal Symptom Rating Scale comparing before and after stimulation (before, 8.7±6.09; after 5.67±3.08; p-value 0.48). This improvement was not observed in the sham group (before, 7.44±4.85; after, 5.67±3.08; p-value 0.16). In the 13C-octanoic acid breath test no significant changes were detectable. CONCLUSIONS: Vagal nerve stimulation is well tolerated with no side effects and may be a promising non-invasive therapy option to improve gastroenteric symptoms in Parkinson's disease.

5-methylcytosine and 5-hydroxymethylcytosine in brains of patients with multiple system atrophy and patients with Parkinson's disease.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of unknown etiology, characterized pathologically by α-synuclein aggregates preferentially found in oligodendroglial cells. DNA methylation has emerged as a mechanism of regulation of α-synuclein expression. Reduced 5-methylcytosine (5-mC) DNA methylation of α-synuclein has been found in the brains of patients with Parkinson's disease (PD). 5-hydroxymethylcytosine (5-hmC) methylation is another epigenetic modification of DNA. It is involved in the de-methylation of DNA, gene regulation, and DNA repair mechanisms. Here, we examined sections of human paraffin-embedded brain tissue from the cerebellum and brain stem, including the substantia nigra pars compacta, of patients with PD (n = 8) and MSA (n = 8) as well as age-matched controls (n = 8). The neocortical tissue of PD patients (n = 10) and controls (n = 10) was also examined. Using immunohistochemistry, we analyzed the expression of 5-mC and 5-hmC with an automatic, rater-independent semi-quantification method. We found a significant upregulation of 5-mC, but not 5-hmC, in cortical sections from PD patients. The brain stem and substantia nigra, and in particular the dopaminergic neurons, showed unchanged levels of both 5-mC- and 5-hmC-immunoreactivity in all groups. In the cerebellum, 5-mC was significantly decreased only in MSA patients in the granule cell layer; in contrast, 5-hmC was significantly upregulated in the cerebellar white matter of both PD and MSA patients. Our study showed different levels of expression of total 5-mC and 5-hmC methylation across different brain regions in PD and for the first time in MSA. Our results indicate that 5-mC may be relevant in MSA. The underlying mechanism of the differential 5-mC and 5-hmC expression remains unclear.

Psychometric Properties of an Abbreviated Version of the Apathy Evaluation Scale for Parkinson Disease (AES-12PD).

BACKGROUND: Apathy is a frequent symptom in Parkinson's disease (PD), substantially aggravating the course of PD. Regarding the accumulating evidence of the key role of apathy in PD, time-efficient assessments are useful for fostering progress in research and treatment. The Apathy Evaluation Scale (AES) is widely used for the assessment of apathy across different nosologies. OBJECTIVE: To facilitate the application of the AES in PD, we reduced the AES to two-thirds its length and validated this abbreviated version. DESIGN: Data sets of 339 PD patients of the DEMPARK/LANDSCAPE study without dementia and depression were randomly split into two samples. Data of sample 1 were used to develop a brief version of the AES (AES-12PD). A cross-validation was conducted in sample 2 and in a subsample of 42 PD patients with comorbid dementia and depressive symptomatology. Receiver operating characteristic analysis was applied to determine the optimal cutoff of the AES-12PD as an indicator of apathy. RESULTS: The AES-12PD featured high internal consistency that was better compared to the AES. The abbreviated scale was well differentiated from motor impairment and cognitive deficits. The AES-12PD cutoff of 27/28 was the optimal cutoff for apathy in PD patients without dementia and depression. The cutoff of 25/26 indicated apathy in PD patients with comorbid dementia and depression. CONCLUSION: Results confirm a high internal consistency and good discriminant validity of the AES-12PD. The AES-12PD represents a reliable tool for the efficient assessment of apathy that can be applied in PD patients with and without dementia and depression.

DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis.

DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson's disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease.

Skewed X-chromosome inactivation and XIST locus methylation levels do not contribute to the lower prevalence of Parkinson's disease in females.

Parkinson's disease (PD) is a degenerative disorder of the nervous system and the cause of the majority of sporadic cases is unknown. Females are relatively protected from PD as compared with males and linkage studies suggested a PD susceptibility locus on the X chromosome. To determine a putative association of skewed X-chromosome inactivation (XCI) and PD, we examined XCI patterns using a human androgen receptor gene-based assay (HUMARA) and did not identify any association of skewed or random X inactivation with clinical heterogeneity among female PD patients. In addition, we sought to determine methylation-specific changes at the X-inactive specific transcript (XIST) locus, which is known to be responsible for initiating X inactivation. We observed a trend towards hypomethylation in the gene body region of the XIST locus in PD females which did not reach significance. Furthermore, we extended our analysis of DNA methylation across the entire X-chromosome which revealed no methylation-specific differences between PD females and healthy controls. Thus, we propose that skewed XCI and methylation levels on the entire X chromosome did not reveal changes which could account for the decreased PD susceptibility in females or suitable to use as a biomarker.