Naturalistic assessment of everyday multitasking in Parkinson's disease with and without mild cognitive impairment.

Objective: Multitasking is an essential part of everyday functioning often not formally assessed by traditional neuropsychological tests. Although individuals with Parkinson's disease (PD) experience both motor and cognitive difficulties, previous research has demonstrated more pronounced functional difficulties with the presence of mild cognitive impairment (PD-MCI). The current study compared individuals with PD-MCI, PD with normal cognition (PD-NC), and healthy controls on a naturalistic task of multitasking, the Day Out Task (DOT). Method: Participants were 38 healthy older adults (HOA), 23 individuals with PD-NC, and 15 individuals with PD-MCI. Participants completed a battery of neuropsychological tasks and the DOT. Informants also completed a self-reported questionnaire of participants' everyday executive functioning. Results: Compared to PD-NC and HOA, participants with PD-MCI were less accurate and efficient and took longer to complete the DOT. After controlling for motor performance, only DOT accuracy remained worse, with poorer accuracy resulted from more subtasks being left incomplete or being completed inaccurately by the PD-MCI group. DOT sequencing was a significant predictor of informant reported everyday dysexecutive symptoms. Conclusions: The findings highlight that individuals with PD-MCI are likely to experience difficulties completing complex everyday tasks due to both motor and cognitive impairments. Clinicians may therefore recommend strategies to support efficiency and accuracy in complex tasks of everyday functioning in treatment considerations.

ALSUntangled #66: antimycobacterial antibiotics.

Several infections have been associated with motor neuron diseases resembling ALS, including species of viruses, bacteria, and parasites. Mycobacterium avium subspecies paratuberculosis (MAP), most known for its probable etiologic association with Crohn's disease, has been suggested as another possible infectious cause of motor neuron disease. Two published case reports describe the successful treatment of ALS-like symptoms with antimycobacterial antibiotics. Both cases had atypical features. Based on these, we believe it would be reasonable to begin performing chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between mycobacteria and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.

A Comparison of Functional Abilities in Individuals with Mild Cognitive Impairment and Parkinson's Disease with Mild Cognitive Impairment Using Multiple Assessment Methods.

OBJECTIVE: This study used multiple assessment methods to examine instrumental activities of daily living (IADLs) performance in individuals with Parkinson's disease with mild cognitive impairment (PD-MCI) compared to individuals with mild cognitive impairment (MCI) and cognitively healthy older adults (HOA). Associations between functional performance and cognition were also examined. METHODS: Eighteen individuals with PD-MCI, 48 individuals with MCI, and 66 HOAs were assessed with multiple IADL measures, including direct observation, a performance-based measure, and self- and informant-report questionnaires. Performance on the direct-observation measure was further characterized by coding for four error types: omissions, substitutions, and inefficient and irrelevant/off-task actions. RESULTS: Both the PD-MCI and MCI groups performed more poorly on the overall score for all IADL measures relative to HOAs. Although the PD-MCI and MCI groups did not differ in overall performance, on the direct-observation measure, the PD-MCI group took longer and made more inefficient and irrelevant/off-task errors relative to the HOA and MCI groups, whereas the MCI group made more omission and substitution errors relative to HOAs. Further, the pattern of cognitive correlates that associated most strongly with the functional measures varied across groups and functional assessment methods. CONCLUSION: Compared to HOAs, PD-MCI and MCI groups demonstrated increased difficulties performing everyday activities, and cognitive and motor abilities differentially contributed to the everyday task difficulties of these two groups.

A Retrospective Cost Analysis of Patients Who Switched from OnabotulinumtoxinA to IncobotulinumtoxinA in a Private Neurology Practice.

BACKGROUND: Botulinum neurotoxin type A (BoNT-A) is an effective treatment for many chronic conditions, but the economic implications of repeated treatments can be a burden on patients. The 3 commercial preparations of BoNT-A types available today are onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA, but no clear differences have been found in clinical efficacy between these 3 type A toxins in blinded comparative studies. OBJECTIVE: To conduct a cost-minimization analysis in a cohort of patients with chronic neurologic conditions who switched treatment from onabotulinumtoxinA to incobotulinumtoxinA. METHODS: The study was a single-center, retrospective review of data from a large, private, neurological practice in Spokane, WA. A comprehensive patient chart review was conducted of all patients who were switched from established onabotulinumtoxinA therapy to incobotulinumtoxinA therapy between 2012 and 2019. The patients were switched at a 1:1-unit ratio. All patients had commercial insurance or Medicare coverage. Dosage, injection intervals, wastage, treatment costs, switchback data, and patient savings program eligibility were evaluated for the period of 1 year before and 1 year after the switch from onabotulinumtoxinA to incobotulinumtoxinA therapy. RESULTS: The most frequently treated indication was cervical dystonia (N = 61; 54.5%), followed by chronic migraine (N = 36; 32.1%). After switching to incobotulinumtoxinA therapy, botulinum toxin wastage was reduced by 87.3% (from 150.9 units to 19.1 units), and the cost was reduced by 32.2% (from $5108 to $3461) per patient annually. A total of 14,635 units in unavoidable wastage and $182,792 in annual botulinum toxin costs were saved as a result of the switch in therapy. Patients remained at consistent dosing intervals after switching to incobotulinumtoxinA therapy. A total of 8 patients switched back to onabotulinumtoxinA treatment during this review, including 3 patients who switched back because of insurance reasons, and 5 who had self-reported efficacy concerns. The 70 commercially insured patients in the study who were eligible for the patient savings program for each of the 2 therapies saved an average of $2076 (241.5%) in annual costs after switching from onabotulinumtoxinA to incobotulinumtoxinA. CONCLUSION: Our findings showed that switching from onabotulinumtoxinA to incobotulinumtoxinA at similar intervals and dosages achieved considerable cost-savings, with a low incidence of switching back.

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 subject's 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.

Gamma knife radiosurgery for movement disorders: a concise review of the literature.

Medication is the predominant method for the management of patients with movement disorders. However, there is a fraction of patients who experience limited relief from pharmaceuticals or experience bothersome side-effects of the drugs. Deep brain stimulation (DBS) and surgical lesioning of the thalamus and basal ganglia are respected neurosurgical procedures, with valued success rates and a very low incidence of complications. Despite these positive outcomes, DBS and surgical lesioning procedures are contraindicated for some patients. Stereotactic radiosurgery with the Gamma Knife (GK) has been used as a lesioning technique for patients seeking a non-invasive treatment alternative and for medication-intolerable patients, who are unable to undergo DBS or lesioning due to comorbid medical conditions. Tremors of various etiologies are treated using GK thalamotomy, which targets the ventralis intermedius nucleus. GK thalamotomy produces favorable outcomes when treating tremors, with success rates ranging from 80-100%. In contrast, GK pallidotomy targets the internal globus pallidus, and is used in treating bradykinesia, rigidity, and dyskinesia. Although radiosurgery has proven beneficial for tremors, radiosurgical pallidotomy for bradykinesia, rigidity, and dyskinesia remains questionable, with mixed success rates in the literature that ranges from 0-87%. We suggest that GK thalamotomy be offered along with other neurosurgical approaches as a feasible treatment option to patients who prefer the non-invasive nature of radiosurgery and to those who are unqualified candidates for the neurosurgical alternatives. Also, we advise that patients with bradykinesia, rigidity, and dyskinesia be educated about the variability in the literature pertaining to GK pallidotomy before proceeding with treatment.

Gamma knife radiosurgery for essential tremor: a case report and review of the literature.

Approximately 5 million people in America are affected by essential tremors (ET), which are classified as a type of benign movement disorder. This disease manifests as tremors that usually occur in the hands, but they may also be present in the head, face, tongue, and lower limbs. Radiofrequency thalamotomy (RF) and deep brain stimulation (DBS) are common invasive procedures with proven track records that are used to treat ET. Although these procedures have high success rates, they still put patients at risk of potential side effects and are invasive by nature. Thalamotomy using the gamma knife (GK) also produces favorable outcomes in treating tremors, without the complications associated with invasive neurosurgery procedures. This report describes the presenting symptoms and extended treatment outcome for a patient with an advanced case of ET, who received GK thalamotomy treatment six years ago. Because of this non-invasive treatment, she regained the ability to paint and live with an improved quality of life. We also discuss and review the relevant literature regarding the risks and benefits of this treatment modality. GK thalamotomy is one effective option for the treatment of ET, and due to its noninvasive nature, it has a different risk profile than neurosurgery. We suggest that GK thalamotomy should be presented as one viable treatment option to all ET patients, and should be recommended to those who would be best served by less invasive treatment techniques.

Characterizing multiple memory deficits and their relation to everyday functioning in individuals with mild cognitive impairment.

The authors evaluated multiple memory processes and explored their contributions to everyday functional limitations in persons with mild cognitive impairment (MCI). Participants included individuals with amnestic MCI, nonamnestic MCI, and healthy older adults. As expected, the amnestic MCI group performed more poorly than the control and nonamnestic MCI groups on a content memory measure. Both MCI groups, however, performed more poorly than controls on the noncontent memory measures of prospective memory, temporal order memory, and source memory. Informants also reported that the MCI groups were experiencing greater difficulty than controls completing instrumental activities of daily living (IADLs). Noncontent memory measures were found to make an independent contribution to IADL performances over and above that of content memory. These findings demonstrate that impairments in memory beyond the traditionally assessed content memory are present in individuals with amnestic MCI and with nonamnestic MCI. The results further show that these noncontent memory processes, which have been linked with executive functioning, play a role in supporting IADLs.

A predictive pharmacophore model of human melanocortin-4 receptor as derived from the solution structures of cyclic peptides.

Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the solution structures for a series of potent agonists for the human melanocortin-4 receptor (hMC4R), based on the cyclic peptide MT-II [Ac-Nle-cyclo-(Asp-Lys) (Asp-His-(D)Phe-Arg-Trp-Lys)-NH2]. Members of this series were designed to improve selectivity for MC4R versus the other melanocortin receptors, and to reduce the flexibility of the side chains. The most selective and rigid analog [penta-cyclo(D-K)-Asp-Apc-(D)Phe-Arg-(2S,3S)-beta-methylTrp-Lys-NH2] was found to be a full agonist of hMC4R with an EC50 of 11nM against hMC4R, and to exhibit 65-fold selectivity against hMC1R. This compound represents the most constrained hMC4R peptide agonist described to date. A beta-turn structure was conserved among all of the cyclic peptides studied. The rigidity of the analogs allowed an exceptionally well-defined pharmacophore model to be derived. This model was used to perform a virtual screen using a library of 1000 drug-like compounds, to which a small set of known potent ligands had been intentionally added. The utility of the model was validated by its ability to identify the known ligands from among this large library.

NMR characterization of interleukin-2 in complexes with the IL-2Ralpha receptor component, and with low molecular weight compounds that inhibit the IL-2/IL-Ralpha interaction.

Nuclear magnetic resonance (NMR) methods were employed to study the interaction of the cytokine Interleukin-2 (IL-2) with the alpha-subunit of its receptor (IL-2Ralpha), and to help understand the behavior of small molecule inhibitors of this interaction. Heteronuclear (1)H-(15)N HSQC experiments were used to identify the interaction surface of (15)N-enriched Interleukin-2 ((15)N-IL-2) in complex with human IL-2Ralpha. In these experiments, chemical shift and line width changes in the heteronuclear single-quantum coherence (HSQC) spectra upon binding of (15)N-IL-2 enabled classification of NH atoms as either near to, or far from, the IL-2Ralpha interaction surface. These data were complemented by hydrogen/deuterium (H/D) exchange measurements, which illustrated enhanced protection of slowly-exchanging IL-2 NH protons near the site of interaction with IL-2Ralpha. The interaction surface defined by NMR compared well with the IL-2Ralpha binding site identified previously using mutagenesis of human and murine IL-2. Two low molecular weight inhibitors of the IL-2/IL-2Ralpha interaction were studied: one (a cyclic peptide derivative) was found to mimic a part of the cytokine and bind to IL-2Ralpha; the other (an acylphenylalanine derivative) was found to bind to IL-2. For the interaction between IL-2 and the acylphenylalanine, chemical shift perturbations of (15)N and (15)NH backbone resonances were tracked as a function of ligand concentration. The perturbation pattern observed for this complex revealed that the acylphenylalanine is a competitive inhibitor-it binds to the same site on IL-2 that interacts with IL-2Ralpha.