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INTRODUCTION: The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit. METHODS: We studied a patient initially diagnosed with SWEDD (based on (18)F-dopa PET) who developed unequivocal PD associated with a leucine-rich repeat kinase 2 p.G2019S mutation. Repeat multitracer PET was performed at 17 years' disease duration, including (+)[11C]dihydrotetrabenazine, [11C](N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (which binds the serotonin transporter), and (18)F-dopa. RESULTS: The patient showed bilateral striatal dopaminergic denervation (right putamen 28% of age-matched normal, left putamen 33%). (18)F-dopa uptake was decreased, particularly on the left (mean 31% of normal vs. 45% on the more affected right side). Serotonin transporter binding was relatively preserved in the putamen (right mean 90% of normal, left 81%) and several cortical regions. CONCLUSIONS: SWEDD can occur in genetically determined PD and may, in some cases, be the result of compensatory nondopaminergic mechanisms operating in early disease.
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Encéfalo/patología , Dopamina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/diagnóstico , Encéfalo/metabolismo , Dopamina/metabolismo , Femenino , Heterocigoto , Humanos , Leucina/metabolismo , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Tomografía de Emisión de Positrones/métodos , CintigrafíaAsunto(s)
Cobre/deficiencia , Derivación Gástrica/efectos adversos , Enfermedades de la Médula Espinal/diagnóstico por imagen , Oligoelementos/deficiencia , Cobre/sangre , Cobre/uso terapéutico , Enfermedades Carenciales/patología , Femenino , Humanos , Persona de Mediana Edad , Enfermedades de la Médula Espinal/sangre , Enfermedades de la Médula Espinal/terapia , Oligoelementos/sangre , Oligoelementos/uso terapéuticoRESUMEN
Background: Vibration of one limb affects motor performance of the contralateral limb, and this may have clinical implications for people with lateralized motor impairments through vibration-induced increase in cortical activation, descending neural drive, or spinal excitability. Objective: The objective of this study was to evaluate the effects of acute biceps brachii tendon vibration on force steadiness and motor unit activity in the contralateral limb of persons with Parkinson's disease. Methods: Ten participants with mild to moderate Parkinson's disease severity performed a ramp, hold and de-ramp isometric elbow flexion at 5% of maximum voluntary contraction with the more-affected arm while vibration was applied to the distal biceps brachii tendon on the contralateral, less-affected arm. Using intramuscular fine wire electrodes, 33 MUs in the biceps brachii were recorded across three conditions (baseline, vibration, and post-vibration). Motor unit recruitment & derecruitment thresholds, discharge rates & variability, and elbow flexion force steadiness were compared between conditions with and without vibration. Results: Coefficient of variation of force and discharge rate variability decreased 37 and 17%, respectively in post-vibration compared with baseline and vibration conditions. Although the motor unit discharge rates did not differ between conditions the total number of motor units active at rest after de-ramp were fewer in the post-vibration condition. Conclusion: Contralateral tendon vibration reduces MU discharge rate variability and enhances force control on the more affected side in persons with Parkinson's disease.
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Introduction: Postural instability increases with age and is exacerbated in neurological disorders such as Parkinson's disease (PD). Reducing the base of support from bipedal to unipedal stance increases center of pressure (CoP) parameters and intermuscular coherence in lower-leg muscles of healthy older adults. To further develop an understanding of postural control in an altered state of neurological impairment, we explored intermuscular coherence in lower-leg muscles and CoP displacement in older adults with PD. Methods: This study measured surface EMG from the medial (MG) and lateral (LG) gastrocnemii, soleus (SOL), and tibialis anterior (TA), and examined EMG amplitude and intermuscular coherence during bipedal and unipedal stance on a force plate with firm (no foam) and compliant (standing on foam) surface conditions in nine older adults with PD (70±5 years, 6 females) and 8 age-matched non-Parkinsonian older adults (5 females). Intermuscular coherence was analyzed between agonist-agonist and agonist-antagonist muscle pairs in the alpha (8-13 Hz) and beta (15-35 Hz) frequency bands. Results: CoP parameters increased from bipedal to unipedal stance in both groups (p < 0.01), but did not increase from the firm to compliant surface condition (p > 0.05). During unipedal stance, CoP path length was shorter in older adults with PD (2027.9 ± 1074.1 mm) compared to controls (3128.5 ± 1198.7 mm) (p < 0.01). Alpha and beta agonist-agonist and agonist-antagonist coherence increased by 28% from bipedal to unipedal stance (p > 0.05), but did not differ between older adults with PD (0.09 ± 0.07) and controls (0.08 ± 0.05) (p > 0.05). The older adults with PD also had greater normalized EMG amplitude of the LG (63.5 ± 31.7%) and TA (60.6 ± 38.4%) during the balance tasks (p > 0.05) than the non-Parkinsonian counterparts. Discussion: Older adults with PD had shorter path lengths during unipedal stance and required greater muscle activation than older adults without PD to perform the tasks, but intermuscular coherence did not differ between the groups. This may be attributable to their early disease stage and high motor function.
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Although plantar flexion force steadiness (FS) is reduced in persons with Parkinson's disease (PD), the underlying causes are unknown. The aim of this exploratory design study was to ascertain the influence of maximal voluntary contraction (MVC) force and gastrocnemius-Achilles muscle-tendon unit behaviour on FS in persons with PD. Nine persons with PD and nine age- and sex-matched non-PD controls (~70 years, 6 females per group) performed plantar flexion MVCs and sub-maximal tracking tasks at 5, 10, 25, 50 and 75% MVC. Achilles tendon elongation and medial gastrocnemius fascicle lengths were recorded via ultrasound during contraction. FS was quantified using the coefficient of variation (CV) of force. Contributions of MVC and tendon mechanics to FS were determined using multiple regression analyses. Persons with PD were 35% weaker during MVC (p = 0.04) and had 97% greater CV (p = 0.01) with 47% less fascicle shortening (p = 0.004) and 38% less tendon elongation (p = 0.002) than controls. Reduced strength was a direct contributor to lower FS in PD (ß = 0.631), and an indirect factor through limiting optimal muscle-tendon unit interaction. Interestingly, our findings indicate an uncoupling between fascicle shortening and tendon elongation in persons with PD. To better understand limitations in FS and muscle-tendon unit behavior, it is imperative to identify the origins of MVC decrements in persons with PD.
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BACKGROUND: Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. METHODS: Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. FINDINGS: We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. INTERPRETATION: LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. FUNDING: Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.
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Encéfalo/metabolismo , Neuronas Colinérgicas/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Acetilcolinesterasa/metabolismo , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Síntomas ProdrómicosRESUMEN
BACKGROUND: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Adulto , Anciano , Encéfalo/metabolismo , Estudios Transversales , Dihidroxifenilalanina/análogos & derivados , Femenino , Heterocigoto , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/genética , Tomografía de Emisión de Positrones/métodos , RadiofármacosRESUMEN
BACKGROUND: Distinguishing the postural re-emergent tremor of Parkinson disease from essential tremor can be difficult clinically. Use of accelerometry to aid diagnosis is limited to laboratory settings. We sought to record and differentiate these tremors using a smart watch device in an outpatient clinic. NEW METHOD: 41 patients were enrolled. Recordings were made with a smart watch device on the predominantly affected hand (all patients), and simultaneously with an analog accelerometer (10 patients) with hands at rest and outstretched. Tremor peak frequency, peak power, and power of the first four harmonics was calculated and compared between the two devices. Mean power at the first four harmonics was calculated and used to classify tremor as parkinsonian or essential. Test characteristics were calculated to compare the device and clinical diagnoses. RESULTS: Mean harmonic peak power was both highly sensitive and specific for distinction of Parkinson disease postural tremor from essential tremor with an optimal threshold for our sample (sensitivity 90.9%, 95% CI 58.7-99.8%; specificity 100%, 95% CI 76.8-100%; Cohen's kappa=0.91, SE=0.08). COMPARISON WITH EXISTING METHODS: The smart watch and analog devices had nearly perfect concordance of peak frequency and proportional harmonic power. The smart watch recordings in clinic took 3-6 min. CONCLUSIONS: A smart watch device can provide accurate and diagnostically relevant information about postural tremor. Its portability and ease of use could help translate such techniques into routine clinic use or to the community.
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Acelerometría , Equipos y Suministros Eléctricos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Acelerometría/instrumentación , Acelerometría/métodos , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Diagnóstico Diferencial , Temblor Esencial/diagnóstico , Temblor Esencial/fisiopatología , Femenino , Mano , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Ambulatorio/instrumentación , Monitoreo Ambulatorio/métodos , Periodicidad , Curva ROC , Sensibilidad y Especificidad , Grabación en VideoRESUMEN
OPINION STATEMENT: When tics caused by Tourette Syndrome cause meaningful impairment for patients, a comprehensive treatment approach includes education of patients, peers, and family, treatment of comorbid behavioral disorders if present, and consideration of behavior therapy and pharmacotherapy for tics themselves. This systematic review and meta-analysis demonstrates that behavior therapies based on Habit Reversal Therapy, including the Comprehensive Behavioral Intervention for Tics are effective in reducing tic severity when compared with supportive psychotherapy. When these behavior therapies are unavailable, Exposure with Response Prevention may also be effective. Both face-to-face and telehealth delivery methods for behavior therapy improve tic severity, and broader distribution of behavior therapy through increased training or telehealth methods is encouraged. High-quality randomized trials comparing behavior therapies for tics with pharmacotherapy are needed.
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OBJECTIVE: The severity of peripheral neuropathy in diabetic patients varies for unclear reasons. Long-term use of metformin is associated with malabsorption of vitamin B(12) (cobalamin [Cbl]) and elevated homocysteine (Hcy) and methylmalonic acid (MMA) levels, which may have deleterious effects on peripheral nerves. The intent of this study was to clarify the relationship among metformin exposure, levels of Cbl, Hcy, and MMA, and severity of peripheral neuropathy in diabetic patients. We hypothesized that metformin exposure would be associated with lower Cbl levels, elevated Hcy and MMA levels, and more severe peripheral neuropathy. RESEARCH DESIGN AND METHODS: This was a prospective case-control study of patients with type 2 diabetes and concurrent symptomatic peripheral neuropathy, comparing those who had received >6 months of metformin therapy (n = 59) with those without metformin exposure (n = 63). Comparisons were made using clinical (Toronto Clinical Scoring System and Neuropathy Impairment Score), laboratory (serum Cbl, fasting Hcy, and fasting MMA), and electrophysiological measures (nerve conduction studies). RESULTS: Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels. Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with these clinical and paraclinical group differences. CONCLUSIONS: Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of, as well as during, metformin therapy to detect potential secondary causes of worsening peripheral neuropathy.