Fernando Pagan

Evaluation of essential tremor with multi-voxel magnetic resonance spectroscopy

The pathologic substrate of essential tremor (ET) remains unknown. The authors studied 10 patients with ET and 10 volunteers using a multislice MR spectroscopy imaging sequence. Left and right cerebellar hemisphere NAA/CR and NAA/Cho ratios were significantly smaller in the ET patients than healthy subjects. The authors’ data suggest that the decreased NAA/Cr and NAA/Cho ratios within the cerebellum may represent an abnormality in neuronal function.

Safety of MRI in patients with implanted deep brain stimulation devices

OBJECTIVE To survey the safety of MRI in PD patients implanted with DBS devices. BACKGROUND MRI in patients with DBS implants is useful to confirm electrode placement, optimize programming and investigating complications. However, several medical centers do not perform MRI studies in DBS patients because of safety concerns. The safety profile of MRI in DBS patients has not been documented in large clinical series. METHODS 42 NPF Centers of Excellence (COEs) were asked to complete a questionnaire on MRI use and DBS. RESULTS Investigators from 40 of 42 (95%) NPF COEs completed the survey and 23 (58%) reported that they were currently performing brain MRI in DBS patients, while 3 (7.5%) had done it in the past. The 17 COEs currently not performing post-operative MRI for DBS listed the following reasons: 1) industry guidelines and/or warnings (53%); 2) decision deferred to outside department (29%); 3) liability/risk/safety (18%); 4) no active DBS program (18%); 5) no available MRI (12%); and 6) insurance and reimbursement concerns (6%). A total of 3304 PD patients with one or more DBS leads had a brain MRI scan, and 177 DBS patients had MRI of other body regions. In one case MRI was associated with an IPG failure without neurological sequelae after IPG replacement. No other complications were reported. CONCLUSIONS these data provide evidence for a favorable risk/benefit ratio for brain MRI in patients with DBS implants. Further studies will need to address whether a re-assessment of more restrictive recommendations (i.e. very low SAR values) may be warranted.

Involvement of Insula and Cingulate Cortices in Control and Suppression of Natural Urges

The physiology of control and suppression of natural urges is not well understood. We used [(15)O]H(2)O positron-emission tomography imaging to identify neural circuits involved in suppression of spontaneous blinking as a model of normal urges. Suppression of blinking was associated with prominent activation of bilateral insular-claustrum regions, right more than left; activation was also found in bilateral anterior cingulate cortex (ACC), supplementary motor areas, and the face area of the primary motor cortex bilaterally. These results suggest a central role for the insula possibly together with ACC in suppression of blinking.

Protection from oxidation enhances the survival of cultured mesencephalic neurons

Oxidative stress has been linked to the destruction of dopaminergic neurons in the substantia nigra and may be a significant factor in both Parkinsons disease and MPTP toxicity. Using primary cultures of embryonic rat mesencephalon and standard immunocytochemical techniques, we have examined the survival of tyrosine hydroxylase-containing (TH+) neurons cultured in the presence of antioxidants and/or in an environment of low oxygen partial pressure. The number of TH+ neurons increased approximately twofold if superoxide dismutase, glutathione peroxidase (GP), or N-acetyl cysteine (NAC) were added to the culture media. Exposure of the neurons to a 5% oxygen environment (38 torr, i.e., 38 mm Hg) also increased the survival of TH+ neurons by about twofold. A dramatic enhancement of survival, however, was seen when NAC was used in combination with the 5% oxygen environment. In this case, the number of TH+ neurons increased fourfold from nontreated controls. Morphological changes were also noted. GP increased the average neurite length while NAC increased the average area of the cell body in the TH+ neuron. These results suggest that manipulation of oxidative conditions by changing the ambient O2 tension or the level of antioxidants promotes survival of TH+ neurons in culture and may have implications for transplantation therapies in Parkinsons disease.

CXCR4 and CXCL12 Expression is Increased in the Nigro-Striatal System of Parkinson’s Disease

Except for a handful of inherited cases related to known gene defects, Parkinson’s disease (PD) is a sporadic neurodegenerative disease of unknown etiology. There is increasing evidence that inflammation and proliferation of microglia may contribute to the neuronal damage seen in the nigro-striatal dopaminergic system of PD patients. Microglia events that participate in neuronal injury include the release of pro-inflammatory and neurotoxic factors. Characterizing these factors may help to prevent the exacerbation of PD symptoms or to remediate the disease progression. In rodents, the nigro-striatal system exhibits high expression of the chemokine receptor CXCR4. Its natural ligand CXCL12 can promote neuronal apoptosis. Therefore, the present study investigated the expression of CXCR4 and CXCL12 in post-mortem brains of PD and control (non-PD) individuals and in an animal model of PD. In the human substantianigra (SN), CXCR4 immunoreactivity was high in dopaminergic neurons. Interestingly, the SN of PD subjects exhibited higher expression of CXCR4 expression and CXCL12 than control subjects despite the loss of dopamine (DA) neurons. This effect was accompanied by an increase in activated microglia. However, results from post-mortem brains may not provide indication as to whether CXCL12/CXCR4 can cause the degeneration of DA neurons. To examine the role of these chemokines, we determined the levels of CXCL12 and CXCR4 in the SN of MPTP-treated mice. MPTP produced a time-dependent up-regulation of CXCR4 that preceded the loss of DA neurons. These results suggest that CXCL12/CXCR4 may participate in the etiology of PD and indicate a new possible target molecule for PD.

Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies

Background: We evaluated the effects of low doses of the tyrosine kinase Abelson (Abl) inhibitor Nilotinib, on safety and pharmacokinetics in Parkinson’s disease dementia or dementia with Lewy bodies. Objectives: The primary outcomes of this study were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory. Methods: Twelve subjects were randomized into 150 mg (n = 5) or 300 mg (n = 7) groups and received Nilotinib orally every day for 24 weeks. Results: This study shows that 150 mg and 300 mg doses of Nilotinib appear to be safe and tolerated in subjects with advanced Parkinson’s disease. Nilotinib is detectable in the cerebrospinal fluid (CSF) and seems to engage the target Abl. Motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes. The CSF levels of homovanillic acid are significantly increased between baseline and 24 weeks of treatment. Exploratory CSF biomarkers were measured. Conclusions: This small proof-of-concept study lacks a placebo group and participants were not homogenous, resulting in baseline differences between and within groups. This limits the interpretations of the biomarker and clinical data, and any conclusions should be drawn cautiously. Nonetheless, the collective observations suggest that it is warranted to evaluate the safety and efficacy of Nilotinib in larger randomized, double-blind, placebo-controlled trials.

Tyrosine Kinase Inhibition Regulates Early Systemic Immune Changes and Modulates the Neuroimmune Response in α-Synucleinopathy.

Objectives Neuro-inflammation is common in α-Synucleinopathies and Tauopathies; and evidence suggests a link between the tyrosine kinase Abl and neurodegeneration. Abl upregulates α-Synuclein and promotes Tau hyper-phosphorylation (p-Tau), while Abl inhibitors facilitate autophagic clearance. Methods A model of α-Synucleinopathy harboring human mutant A53T α-Synuclein and exhibits concomitant increase in murine p-Tau was used to determine the immunological response to Abl inhibition. Results Age-dependent alterations of brain immunity, including loss of IL-10 and decreased levels of IL-2 and IL-3 were observed in old A53T mice. Brain CCL2 and CCL5 were decreased, but CX3CL1 remained constantly elevated. Young A53T mice exhibited differential systemic and central immune profiles in parallel with increased blood markers of adaptive immunity, suggesting an early systemic immune response. Tyrosine kinase inhibitors (TKIs), including nilotinib and bosutinib reduced brain and peripheral α-Synuclein and p-Tau and modulated blood immunological responses. TKIs did not affect brain IL-10, but they changed the levels of all measured blood immune markers, except CX3CL1. TKIs altered microglia morphology and reduced the number of astrocyte and dendritic cells, suggesting beneficial regulation of microglia. Conclusions These data indicate that tyrosine kinase inhibition affects neuro-inflammation via early changes of the peripheral immune profile, leading to modulation of the neuro-immune response to α-Synuclein and p-Tau.

An update on the use of botulinum toxin therapy in Parkinson's disease.

Botulinum toxin (BoNT) has gained widespread use in a variety of neurological conditions. Parkinson’s disease is a complex neurodegenerative disorder manifested by motor and non-motor symptoms that can cause significant disability. BoNT has been used to effectively treat a variety of symptoms related to Parkinson’s disease. This review will examine the current therapeutic indications of BoNT use in the following disorders related to Parkinson’s disease: cervical dystonia, blepharospasm and lid apraxia, focal hand dystonia, foot dystonia, laryngeal dystonia, oromandibular dystonia, camptocormia, hand and jaw tremor, sialorrhea, hyperhidrosis, dysphagia, constipation, and overactive bladder.

Prospective Study Evaluating IncobotulinumtoxinA for Cervical Dystonia or Blepharospasm: Interim Results from the First 145 Subjects with Cervical Dystonia

Background We report the interim results from XCiDaBLE, a large, prospective, observational “naturalistic” study evaluating Xeomin® (incobotulinumtoxinA) for Cervical Dystonia or BLEpharospasm in the United States. Methods Subjects (≥ 18 years old) with cervical dystonia (CD) are followed for two treatment cycles and monitored via Interactive Voice/Web Response. The subjects physician must have chosen to treat with incobotulinumtoxinA prior to and independent of enrollment in this study. Subject-reported scales include the Subject Global Impression-Severity and Improvement and Cervical Dystonia Impact Profile (CDIP-58), and Work Productivity and Quality of Life (QoL) are assessed by means of an employment questionnaire and work history and the SF-12v2 Health Survey (SF-12v2). Subjects are seen by the investigator for three visits, which include a baseline visit (including the first injection), a second injection visit, and a final study visit (12 weeks after the second injection). Results This ongoing study includes 145 subjects with a diagnosis of CD. The majority were female (82.3%) and white (91.0%) and had previously been treated with botulinum toxins (77.2%). There were 106 employed at the time of disease onset, but 12.6 years later only 44% were still employed at the time of enrolment into the study, and 20% were either receiving or seeking disability benefits. The mean total dose/treatment of CD was 225.2 units for the first injection. The CDIP-58 total score was significantly improved 4 weeks after the first injection compared to baseline (p≤0.0001). Most subjects noted improvement in their global impression assessment. No new or unexpected adverse events occurred. Discussion The results from these interim analyses confirm previous controlled, single-dose studies of incobotulinumtoxinA in terms of efficacy and safety.

A guide to dosing in the treatment of cervical dystonia and blepharospasm with Xeomin®: A new botulinum neurotoxin A

Xeomin(®) (incobotulinumtoxinA; Merz Pharmaceuticals, Frankfurt am Main, Germany) was first introduced in Germany for movement disorders in 2005. In 2010, it was approved for use in the United States by the FDA for the treatment of cervical dystonia (CD) and blepharospasm. It is a unique botulinum type A formulation free of any complexing proteins and contains only the pure 150 kD neurotoxin. Thus, the formation of neutralizing antibodies is not induced even after long-term treatment. The purpose of this report is to review the safety profile and dosing schedule for Xeomin for the treatment of CD and blepharospasm. The recommended dose for patients with CD is 120 U/treatment, with administration intervals normally between 3 and 6 months. However, clinical studies have found Xeomin to be safe and effective at doses up to 400 U in both previously treated and treatment-naïve patients. The recommended starting dose in patients with blepharospasm is 2.5-5.0 U/injection site. Patients can be switched using a 1:1 conversion ratio from Botox(®) (onabotulinumtoxinA, Allergen Inc., Irvine, CA, USA) to Xeomin without any loss of efficacy or safety concerns. Xeomin does not differ from Botox in terms of its potency, onset, diffusion profile, or duration and waning of effect. It is the only botulinum treatment that is stable for up to 3 years at room temperature. Xeomin offers a new and important treatment option for movement disorders.