Parkinson Disease: Suchowersky O

Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ, Anonymous00044. · University of Calgary, Calgary, AB, Canada. · Neurology. · Pubmed #16606908 No free full text.

Abstract: OBJECTIVE: To define key issues in the management of Parkinson disease (PD) relating to neuroprotective strategies and alternative treatments, and to make evidence-based treatment recommendations. METHODS: Two clinical questions were identified. 1) In a patient diagnosed with PD, are there any therapies that can slow disease progression? 2) Are there any nonstandard pharmacologic or nonpharmacologic therapies that have been shown to improve motor function in PD? Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence. RESULTS AND CONCLUSIONS: 1. Levodopa does not appear to accelerate disease progression. 2. No treatment has been shown to be neuroprotective. 3. There is no evidence that vitamin or food additives can improve motor function in PD. 4. Exercise may be helpful in improving motor function. 5. Speech therapy may be helpful in improving speech volume. 6. No manual therapy has been shown to be helpful in the treatment of motor symptoms, although studies in this area are limited. Further studies using a rigorous scientific method are needed to determine efficacy of alternative therapies.

Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ, Anonymous00043. · University of Calgary, AB, Canada. · Neurology. · Pubmed #16606907 No free full text.

Abstract: OBJECTIVE: To define key issues in the diagnosis of Parkinson disease (PD), to define features influencing progression, and to make evidence-based recommendations. Two clinical questions were identified: 1) Which clinical features and diagnostic modalities distinguish PD from other parkinsonian syndromes? 2) Which clinical features predict rate of disease progression? METHODS: Systematic review of the literature was completed. Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence. RESULTS AND CONCLUSIONS: 1. Early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction are probably useful in distinguishing other parkinsonian syndromes from Parkinson disease (PD). 2. Levodopa or apomorphine challenge and olfactory testing are probably useful in distinguishing PD from other parkinsonian syndromes. 3. Predictive factors for more rapid motor progression, nursing home placement, and shorter survival time include older age at onset of PD, associated comorbidities, presentation with rigidity and bradykinesia, and decreased dopamine responsiveness. Future research into methods for earlier and more accurate diagnosis of the disease and identification and clarification of predictive factors of rapid disease progression is warranted.

Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. · No affiliation provided · Neurology. · Pubmed #11781398 No free full text.

Abstract: In 1993, the last AAN Practice Parameter on medical treatment of Parkinson's disease (PD) concluded that levodopa was the most effective drug for management of this disorder. Since then, a number of new compounds including non-ergot dopamine agonists (DA) and sustained-release levodopa have been released and studied. Thus, the issue of treatment in de novo PD patients warrants reexamination. Specific questions include: 1) does selegiline offer neuroprotection; 2) what is the best agent with which to initiate symptomatic treatment in de novo PD; and 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review using MEDLINE, EMBASE, and the Cochrane Library was performed to identify all human trials in de novo PD between 1966 and 1999. Only articles that fulfilled class I or class II evidence were included. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit (level A, class II evidence) with no evidence for neuroprotective benefit (level U, class II evidence). 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used (level A, class I and class II evidence). Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia. 3) No evidence was found that initiating treatment with sustained-release levodopa provides an advantage over immediate-release levodopa (level B, class II evidence).

Suchowersky O. · No affiliation provided · Nat Clin Pract Neurol. · Pubmed #18769371 No free full text.

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Suchowersky O. · No affiliation provided · Can J Neurol Sci. · Pubmed #17803021 No free full text.

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Suchowersky O. · No affiliation provided · Nat Clin Pract Neurol. · Pubmed #16932605 No free full text.

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Lang AE, Miyasaki J, Olanow CW, Stoessl AJ, Suchowersky O. · Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Canada. · Can J Neurol Sci. · Pubmed #16225167 No free full text.

Abstract: There are numerous concerns related to treatment choices involving early dopaminergic therapy in Parkinson's disease. These include the effect on the underlying progression of the neurodegenerative process as well as the development of motor complications such as fluctuations and dyskinesias. A number of recent basic and clinical studies have provided new insights but have also added confusion and controversy. This report summarizes presentations and discussion dealing with these issues from a one-day symposium involving Canadian Movement Disorders neurologists.

Suchowersky O. · Movement Disorders Program, University of Calgary, Area 3, Health Sciences Centre, 3350 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. · Curr Neurol Neurosci Rep. · Pubmed #12044250 No free full text.

Abstract: Parkinson's disease, a common neurodegenerative disorder, results in significant morbidity 10 to 15 years after disease onset and increased mortality. Levodopa is the mainstay of therapy and provides benefit for the duration of the illness. However, within 5 years, up to 50% of individuals develop fluctuations, including dyskinesias, wearing off, and "on/off" effects. Optimal management of Parkinson's disease patients requires careful titration of medications, with use of polypharmacy, including levodopa, dopamine agonists, catechol-O-methyltransferase inhibitors, amantadine, and anticholinergics in order to maintain good motor function and quality of life. With advancing disease, problems such as dysphagia, dysarthria, and gait and balance abnormalities occur, which are not responsive to dopaminergic medication. Due to extradopaminergic neuronal system degeneration, autonomic dysfunction can also be prominent. Recognition and management of these problems is helpful in improving quality of life in late-stage disease. In very late stages, dementia may complicate treatment, requiring discontinuation of combination therapy and use of low-dose levodopa with atypical neuroleptics.

Guttman M, Suchowersky O. · Department of Medicine, University of Toronto, Ontario, Canada. · Can J Neurol Sci. · Pubmed #10451761 No free full text.

Abstract: Over the past decade, management of Parkinson's disease has changed significantly due to the expansion of medical and surgical treatment modalities. Neurologists now have the ability (and the challenge) of choosing from multiple medications to devise an individual management strategy for each patient depending on his/her clinical symptoms and needs. Several different surgical therapies are also available. The topics covered in this supplement have highlighted the new options that are now available, as well as the treatments that have been in clinical usage. This review attempts to synthesize the information that is currently available in an attempt to help clinical neurologists make the appropriate choice for their patients.

Rivest J, Barclay CL, Suchowersky O. · Centre Universitaire de Santé de l'Estrie, Fleurimont, Quebec, Canada. · Can J Neurol Sci. · Pubmed #10451758 No free full text.

Abstract: The COMT inhibitors, tolcapone and entacapone, are a new class of Parkinson's medications. By inhibiting the enzyme catechol-o-methyl-transferase (COMT), they prevent peripheral degradation of levodopa, allowing a higher concentration to cross the blood-brain barrier. Pharmacokinetic studies have shown that both tolcapone and entacapone significantly prolong the elimination half life, and increase the area under the curve of levodopa without increasing C max. Clinical studies with COMT inhibitors have shown benefit in both stable and fluctuating PD patients with improvement in motor function with lower levodopa doses. Fluctuating patients also had increased "on" time and reduced "wearing off". Side effects were most commonly related to increased dopaminergic stimulation. Specific side effects included diarrhea and elevated liver enzymes. The recent reports of three cases of fulminant hepatitis with the use of tolcapone has led many countries to remove this compound from their market. Concerns about a possible class effect should impose close monitoring of liver function tests with the use of any of the nitrocatechols.

Mendis T, Suchowersky O, Lang A, Gauthier S. · University of Ottawa, Ottawa Civic Hospital, SCO Hospitals, ON. · Can J Neurol Sci. · Pubmed #10352867 No free full text.

Abstract: The management of Parkinson's disease has undergone recent changes with the advent of new therapies, both pharmacotherapy and surgery. Available interventions are discussed. Levodopa remains the mainstay of therapy. New drugs include the dopamine agonists and COMT inhibitors. New dopamine agonists which may have a levodopa "sparing effect;" it has been suggested that some of the drugs should be considered as first line treatments for newly diagnosed Parkinson's disease patients. We review roles of these drugs. The concept of neuroprotection in neurodegenerative disorders such as Parkinson's disease became popular in the mid 1980s and it is hoped that eventually therapy will be directed at slowing progression of the disease. A great deal more work needs to be done before a suitable agent is identified as being neuroprotective. Potential neuroprotective agents are reviewed. Surgical therapies for Parkinson's disease consisting of various forms of lesion surgery as well as stimulation procedures are reviewed. Complications of drug therapy include motor problems such as motor response fluctuations, as well as psychiatric complications including levodopa-induced psychosis. Atypical neuroleptic agents and ECT for psychiatric syndromes associated with Parkinson's disease are discussed. Algorithms for the management of early disease as well as the management of psychosis in Parkinson's disease are included. Treatment options for advanced disease are tabulated.

Doan JB, Melvin KG, Whishaw IQ, Suchowersky O. · Department of Kinesiology and Physical Education, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada. · Behav Brain Res. · Pubmed #18692094 No free full text.

Abstract: Previous studies have described limb and hand movement abnormalities in a reach-to-eat task in advanced Parkinson's disease (PD) and animal models of PD. The present study was directed toward examining reach-to-eat movements in early PD patients untreated with medication, along with a follow-up examination of a PD patient sub-group who were treated with a symptomatically stable dosage of dopamine replacement. Analysis of the reach-to-eat movement was made using blinded assessment under a validated scoring system, and comparisons were made on the total reach score and reach sub-component scores. In both examinations, PD patients had unilateral deficits or significant deficit asymmetry, as indicated by Unified Parkinson's Disease Rating Scale (UPDRS) scores. UPDRS motor scores were higher for the most-affected side of the body (mean scores of 10.45 and 4.25 for more- and less-affected upper limbs, respectively), whereas reach scores were equivalently impaired for the two sides (median scores of 12.35 and 12.56 for more- and less-affected limbs, respectively). These differences between clinical and experimental assessments of motor impairments persisted among early PD patients treated with medication. Thus, functional reaching shows bilateral and symmetrical abnormalities in early PD patients, even when clinical assessment shows asymmetrical or even unilateral impairment. These findings suggest that functional qualitative reaching evaluation is a sensitive test in early PD, and that significant bilateral abnormalities in reach function are present even in pre-clinical stages of the disease.

Haffenden A, Khan U, Kiss ZH, Suchowersky O. · Movement Disorders and Therapeutic Brain Stimulation Program, Hotchkiss Brain Institute, University of Calgary, Alberta, Canada. · Parkinsonism Relat Disord. · Pubmed #17368072 No free full text.

Abstract: The Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (ADL) items have been described as reflecting both disability (true ADL items) and impairment (rather than ADLs). As a result of combining these scores, UPDRS part II scores may not accurately reflect the impact of surgery on ADLs [Hariz G.M., Lindberg M., Hariz M.I., Bergenheim A.T. Does the ADL part of the unified Parkinson's disease rating scale measure ADL? An evaluation in patients after pallidotomy and thalamic deep brain stimulation. Mov Disord 2003;18:373-81.]. The goal of the present study was to assess the metric properties of the ADL section of the UPDRS in terms of its ability to measure surgical change. We tested the effects of unilateral pallidotomy (N=14) and bilateral subthalamic nucleus (STN) DBS (N=11) on both disability and impairment components of the UPDRS-II at uniform follow-up assessment periods of 6 months and 1 year, with a subset of pallidotomy patients (N=9) re-assessed at 2 years. Across the follow-up periods in both patient groups, items identified as best reflecting disability showed significant improvement from pre-surgical levels, whereas items representing impairment showed no overall change. Consistent with this, change in total ADL scores was tempered by the inclusion of the impairment items. Because the measurement of a patient's functional status is important in determining the effectiveness of an intervention, analysis of appropriate items from the UPDRS ADL section is imperative.

Doan J, Whishaw IQ, Pellis SM, Suchowersky O, Brown LA. · Department of Kinesiology, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada. · J Mot Behav. · Pubmed #16436362 No free full text.

Abstract: Parkinson's disease (PD) patients can perform many daily activities, but movement deficits are evident. Those deficits may be increased when the required movement is constrained in accuracy. Variable improvements in performance with PD medication have been demonstrated, and sensitivity to task constraint has been evident in some studies. The authors quantified both specific movement deficits and improvements for PD patients in a reaching task. PD patients (N=8) both on and off medication showed a need for greater ongoing control in movements with higher task-accuracy constraints. Increased task-accuracy constraints further compromised movement timing and structure among PD patients who were off medication, suggesting that unmedicated PD patients may typically compensate by using more conscious control of movement, resulting in increased slowing and segmentation of components when higher task accuracy is required.

Lun V, Pullan N, Labelle N, Adams C, Suchowersky O. · University of Calgary Sport Medicine Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada. · Mov Disord. · Pubmed #15838853 No free full text.

Abstract: The effects of a self-supervised home exercise program and a physiotherapist-supervised exercise program on motor symptoms in Parkinson's disease (PD) patients were compared in a prospective single-blinded clinical trial. Nineteen subjects (6 women, 13 men; mean age, 65 +/- 8 years) with Hoehn and Yahr Stages 2 to 3 were recruited. Subjects were self-selected into an 8-week exercise program that was self-supervised (HOME group) or physiotherapist-supervised (PT group). The primary outcome measurement was the Unified Parkinson's Disease Rating Scale (UPDRS) Motor subsection score (UPDRSm). The secondary outcome measurements were the Berg Balance Scale, Timed Up and Go Test, UPDRS Total score, and the Activities-specific Balance Confidence Scale. All outcomes were assessed at baseline and at 8 and 16 weeks after the start of the study. The investigators were blinded to the subject treatment group. Bonferroni-corrected paired Student's t test was used to evaluate the change in the UPDRSm from baseline to 8 weeks. Ninety-five percent confidence intervals (CI) were calculated for the change in the secondary outcome measurements from baseline to 8 weeks. There was statistically significant and equal decrease in the UPDRSm from baseline to 8 weeks in both treatment groups. There was no difference in the 95% CI in the change of the secondary outcome measurements. A self-supervised exercise program was found to have similar effectiveness as a physiotherapist-supervised exercise program in improving motor symptoms in PD patients. This finding is important in the counseling of PD patients regarding adjunctive treatment of motor symptoms of PD with exercise.

Melvin KG, Doan J, Pellis SM, Brown L, Whishaw IQ, Suchowersky O. · Department of Clinical Neurosciences, Faculty of Medicine, Movement Disorders Program, Foothills Hospital, University of Calgary, Area 33350, Hospital Dr NW, Calgary, Alta., Canada T2N 4N1. · Behav Brain Res. · Pubmed #15836914 No free full text.

Abstract: OBJECTIVE: To determine effects of dopaminergic medication and pallidal deep brain stimulation (DBS) on skilled reach in Parkinson's disease (PD). BACKGROUND: PD is a neurodegenerative disorder affecting motor control. While speed and execution of movements are improved by L-dopa, not all motor symptoms are alleviated. Little is known about the effects of DBS or medication on reaching. DESIGN METHOD: Eight PD patients with unilateral pallidal DBS reached with the contra-lateral hand for a piece of food, placing it in the mouth, and returning to starting position. Testing was performed on no treatment, medication only, DBS only, and combined treatment. Reaches were digitally recorded and analyzed on a 21 point scale adapted from Eshkol-Wachman Notation. Analysis was blinded, with patients compared to age-matched controls. RESULTS: Patients were tested 6-13 months after surgery. All showed significant improvement clinically and in UPDRS (III) scores. The following data were obtained on the reaching scale: normal controls 16.5-21.0 (mean 18.3), no treatment 3.0-12.5 (mean 7.4), medication only 7.0-14.0 (mean 10.3), DBS only 4.5-16.0 (mean 9.2), combined treatment 4.0-15.0 (mean 9.5). The difference between controls and all treatment groups was statistically significant (P<0.005). All aspects of reach were compromised. No significant differences were found among the four conditions. CONCLUSIONS: This study is consistent with accumulating evidence that some aspects of motor performance in PD patients, such as reaching, are resistant to L-dopa. Also, pallidal DBS does not improve those parameters that are resistant to L-dopa, either alone or in combination with medication.

Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A, Anonymous00163. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Arch Neurol. · Pubmed #15262734 links to  free full text

Abstract: BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Furtado S, Farrer M, Tsuboi Y, Klimek ML, de la Fuente-Fernández R, Hussey J, Lockhart P, Calne DB, Suchowersky O, Stoessl AJ, Wszolek ZK. · Movement Disorder Clinic, Department of Clinical Neurosciences, University of Calgary, Alberta, Canada. · Neurology. · Pubmed #12451209 No free full text.

Abstract: The authors describe an Alberta family with levodopa-responsive parkinsonism without cerebellar abnormalities. Genetic testing showed expanded repeats for SCA-2; other mutations for parkinsonism were excluded. The expanded allele shows interruption of the CAG repeat with CAA. PET in two affected members showed reduced fluorodopa uptake in striatum and normal raclopride binding. Families with autosomal dominant, levodopa-responsive parkinsonism should be tested for the SCA-2 mutation.

Whishaw IQ, Suchowersky O, Davis L, Sarna J, Metz GA, Pellis SM. · Canadian Centre for Behavioural Neuroscience, The University of Lethbridge, 4401 University Drive, Alberta, Canada T1K 3M4. · Behav Brain Res. · Pubmed #12110450 No free full text.

Abstract: Animal (monkey, rat, mouse) models are widely used to investigate degenerative processes and potential therapeutic treatments for human Parkinson's disease (PD). One task that has proved useful in these investigations is a reach-to-grasp task (skilled reaching) in which an animal reaches for a piece of food that it then consumes. Rats with extensive unilateral Dopamine depletions are impaired in using the contralateral limb. The qualitative features of posture, lifting and advancing the limb, pronating the paw to grasp food, and in withdrawing and supinating the paw to place the food in the mouth are impaired, as is reaching success. Humans with PD are often described as having poor manual dexterity that worsens as the disease progresses. As there have been no detailed comparisons of reaching movements in the animal models and in PD subjects, the following descriptive analysis was performed. Ten subjects with PD, eight age matched controls and 14 young normal subjects were studied as they used a natural movement of reaching for a small piece of food that they then placed in the mouth to eat. The reaching movements were described using Eshkol-Wachman Movement Notation (EWMN), supplemented with kinematic analyses. From this description, a 21-point rating scale was devised to describe the component movements of the reach. Movements included: orienting the head and eyes to the target, adjusting posture, lifting the hand, shaping and aiming the digits to the target, pronating the hand to grasping the food with a pincer grip, lifting and supinating the hand to transporting the food to the mouth, and further supinating the hand and opening the digits to place food in the mouth, and finally returning the hand to the starting position. Analysis indicated that most aspects of the reaching movements of the PD subjects were significantly different relative to both young control subjects and old control subjects. As compared to the control groups, postural and reaching components of the movements were fragmented, movements were achieved using more proximal segments of the body, and rotatory movements of the hand were limited. The PD subjects did use a pincer grasp to obtain the food, but the grasp was less independent of other digit movements than was observed in the control subjects. These results are discussed in terms of a homology to impairments displayed animal models of PD.

Suchowersky O, Bailey P, Pourcher E, Bulger L, Facciponte G. · Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Alberta, Canada. · Clin Neuropharmacol. · Pubmed #11479392 No free full text.

Abstract: The efficacy and safety of two dosages of tolcapone were compared in a 12-week crossover trial involving 118 nonfluctuating patients with PD on a stable dose of levodopa (L-Dopa). At trial onset, all patients received open-label tolcapone 100 mg three times daily for 4 weeks. At week 4, 116 eligible patients entered an 8-week double-blind treatment period and were randomized to receive tolcapone three times daily at either 100 mg (group 1; n = 58) or 200 mg (group 2; n = 58) until week 8, followed by the alternative tolcapone dosage until week 12. Ratings included Unified Parkinson's Disease Rating Scale (UPDRS), Schwab & England, and patient diaries, assessed at baseline and at 4, 8, and 12 weeks. At week 4, the investigator's global assessment (IGA) of efficacy showed improvement in 76% of patients. The mean total daily L-Dopa dose and mean UPDRS scores for subscales II and III decreased significantly (p < 0.001). During the double-blind treatment period, IGA showed improvements at either or both dosages in 61% of patients; further changes in other efficacy variables were minimal and were similar with both tolcapone dosages. The most frequent adverse events were dopaminergic (nausea and dyskinesia); the most frequent nondopaminergic adverse event was diarrhea. The incidence of adverse events during double-blind treatment was slightly higher with tolcapone 200 mg three times daily (33%) than with tolcapone 100 mg three times daily (24%). The authors conclude that tolcapone dosages of 100 mg three times daily and 200 mg three times daily are well tolerated and equally effective in improving function in L-Dopa-treated nonfluctuating patients with PD.

Shoulson I, Penney J, McDermott M, Schwid S, Kayson E, Chase T, Fahn S, Greenamyre JT, Lang A, Siderowf A, Pearson N, Harrison M, Rost E, Colcher A, Lloyd M, Matthews M, Pahwa R, McGuire D, Lew MF, Schuman S, Marek K, Broshjeit S, Factor S, Brown D, Feigin A, Mazurkiewicz J, Ford B, Jennings D, Dilllon S, Comella C, Blasucci L, Janko K, Shulman L, Wiener W, Bateman-Rodriguez D, Carrion A, Suchowersky O, Lafontaine AL, Pantella C, Siemers E, Belden J, Davies R, Lannon M, Grimes D, Gray P, Martin W, Kennedy L, Adler C, Newman S, Hammerstad J, Stone C, Lewitt P, Bardram K, Mistura K, Miyasaki J, Johnston L, Cha JH, Tennis M, Panniset M, Hall J, Tetrud J, Friedlander J, Hauser R, Gauger L, Rodnitzky R, Deleo A, Dobson J, Seeberger L, Dingmann C, Tarsy D, Ryan P, Elmer L, Ruzicka D, Stacy M, Brewer M, Locke B, Baker D, Casaceli C, Day D, Florack M, Hodgeman K, Laroia N, Nobel R, Orme C, Rexo L, Rothenburgh K, Sulimowicz K, Watts A, Wratni E, Tariot P, Cox C, Leventhal C, Alderfer V, Craun AM, Frey J, McCree L, McDermott J, Cooper J, Holdich T, Read B, Anonymous00161. · No affiliation provided · Neurology. · Pubmed #11222787 No free full text.

Abstract: BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Chong DJ, Suchowersky O, Szumlanski C, Weinshilboum RM, Brant R, Campbell NR. · Department of Clinical Neurosciences, University of Calgary, Alberta, Canada. · Clin Neuropharmacol. · Pubmed #10895397 No free full text.

Abstract: Patients with Parkinson's Disease (PD) have a variable response to tolcapone, a catechol-O-methyltransferase (COMT) inhibitor. In addition, a subset of patients develop severe diarrhea as a side effect. Two codominant alleles for the COMT gene exist, coding for low and high activity, resulting in low-, medium-, and high-activity genotypes. This study investigates the relationship between this variation in genotype and clinical effects in patients with PD taking tolcapone. To investigate the relationship between COMT polymorphism and clinical response, 24 patients who completed tolcapone clinical trials provided blood samples for COMT genotype analysis. Change in levodopa dose and United Parkinson Disease Rating Scale (UPDRS) Part III (motor subscale) were analyzed at baseline, at 1-2 weeks, and 6 months after initiation of tolcapone. Genotype analysis was performed on seven patients who had diarrhea as a side effect. There was no significant correlation between genotype and improvement in UPDRS score (p = 0.29) according to a linear models approach that adjusted for the subject's severity of PD, tolcapone dose (either 100 or 200 mg three times daily) and initial differences in baseline scores. No significant difference was seen in change in daily levodopa intake and genotype. There was also no relation between diarrhea and COMT genotype. These results indicate that, in the treatment of Parkinson's disease, COMT genotype is not a major contributor to the clinical response to tolcapone.

Latourelle JC, Sun M, Lew MF, Suchowersky O, Klein C, Golbe LI, Mark MH, Growdon JH, Wooten GF, Watts RL, Guttman M, Racette BA, Perlmutter JS, Ahmed A, Shill HA, Singer C, Goldwurm S, Pezzoli G, Zini M, Saint-Hilaire MH, Hendricks AE, Williamson S, Nagle MW, Wilk JB, Massood T, Huskey KW, Laramie JM, DeStefano AL, Baker KB, Itin I, Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn DJ, Chinnery PF, Pramstaller PP, Al-hinti J, Moller AT, Ostergaard K, Sherman SJ, Roxburgh R, Snow B, Slevin JT, Cambi F, Gusella JF, Myers RH. · Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA. · BMC Med. · Pubmed #18986508 links to  free full text

Abstract: BACKGROUND: We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. METHODS: A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. RESULTS: Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. CONCLUSION: Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Toth C, Brown MS, Furtado S, Suchowersky O, Zochodne D. · Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. · Mov Disord. · Pubmed #18785232 No free full text.

Abstract: The presence and potential etiologies of peripheral neuropathy (PN) in patients with Parkinson's Disease (PD) is unknown. We examined for presence of PN in patients with PD. From a PD patient population of 500 patients screened for features of symptomatic PN, patients were further selected for clinical, electrophysiological, and laboratory studies related to PN. This PD patient population with idiopathic PN (PD-IPN) was compared to a group of PD patients without PN (PD-only), and a large group of patients without PD with idiopathic PN (IPN) for abnormalities in Cbl, fasting homocysteine (Hcy), and fasting methylmalonic acid (MMA) levels. PD-IPN and IPN patients identified with abnormalities in Cbl, Hcy, or MMA levels were treated with intramuscular Cbl for 1 to 2 years. Of 49 PD patients with symptomatic PN, 34 patients (69%) had PD-IPN, and 32/34 (94%) had abnormal Hcy or MMA levels as compared to 26/258 (10%) of IPN patients. Cumulative lifetime L-dopa dosage and fasting MMA levels were associated with PN severity. Cbl therapy led to improvements in Hcy and MMA levels in all groups, and PN in PD-IPN patients stabilized during therapy. PN in PD patients may be associated with iatrogenic Cbl metabolic abnormalities. Alternatively PN may be a peripheral nervous system manifestation of PD.

McNicoll CF, Latourelle JC, MacDonald ME, Lew MF, Suchowersky O, Klein C, Golbe LI, Mark MH, Growdon JH, Wooten GF, Watts RL, Guttman M, Racette BA, Perlmutter JS, Ahmed A, Shill HA, Singer C, Saint-Hilaire MH, Massood T, Huskey KW, DeStefano AL, Gillis T, Mysore J, Goldwurm S, Pezzoli G, Baker KB, Itin I, Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn DJ, Chinnery PF, Pramstaller PP, Al-Hinti J, Moller AT, Ostergaard K, Sherman SJ, Roxburgh R, Snow B, Slevin JT, Cambi F, Gusella JF, Myers RH. · Department of Neurology, Boston University School of Medicine, Boston University, Boston, Massachusetts 02118, USA. · Mov Disord. · Pubmed #18649400 No free full text.

Abstract: The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.