Parkinson Disease: Lang AE

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).

Lang AE, Mikulis D. · No affiliation provided · Neurology. · Pubmed #19129504 No free full text.

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Lang AE, Obeso JA. · No affiliation provided · Ann Neurol. · Pubmed #15174009 No free full text.

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Marras C, Lang AE. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #12531932 links to  free full text

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Ludolph AC, Kassubek J, Landwehrmeyer BG, Mandelkow E, Mandelkow EM, Burn DJ, Caparros-Lefebvre D, Frey KA, de Yebenes JG, Gasser T, Heutink P, Höglinger G, Jamrozik Z, Jellinger KA, Kazantsev A, Kretzschmar H, Lang AE, Litvan I, Lucas JJ, McGeer PL, Melquist S, Oertel W, Otto M, Paviour D, Reum T, Saint-Raymond A, Steele JC, Tolnay M, Tumani H, van Swieten JC, Vanier MT, Vonsattel JP, Wagner S, Wszolek ZK, Anonymous00107. · Department of Neurology, University of Ulm, Ulm, Germany. · Eur J Neurol. · Pubmed #19364361 No free full text.

Abstract: Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Lang AE. · Toronto Western Hospital, University of Toronto, Canada. · Neurology. · Pubmed #19221313 No free full text.

Abstract: The questions of when and how to start treatment for Parkinson disease (PD) remain extremely challenging. A variety of treatment- and patient-related factors must be taken into account when making these decisions. Ideally, neuroprotective therapy would be started at the time of diagnosis. However, no treatment has been unequivocally shown to modify disease progression, and those that have some evidence for this effect all provide confounding symptomatic benefits, which may also be important to supplement faltering compensatory mechanisms within the basal ganglia. Dopamine agonists are clearly associated with a reduction in the incidence of dyskinesias in the early years, but it is not certain that this translates into long-term benefit. In addition, a number of nonmotor side effects are more frequently associated with dopamine agonists than with levodopa. This review will highlight these and other issues that must be considered when deciding on the early treatment of PD.

Lim SY, Fox SH, Lang AE. · Movement Disorders Centre, Toronto Western Hospital, 399 Bathurst St, Toronto, Ontario M5T 2S8, Canada. · Arch Neurol. · Pubmed #19204152 No free full text.

Abstract: In recent years, there has been increasing recognition of the features of Parkinson disease that are not related to nigrostriatal dopamine deficiency. This review addresses selected clinical, anatomic, pathologic, and biochemical correlates of the early premotor symptoms of Parkinson disease, later nonmotor fluctuations, and advanced dopa-unresponsive motor and nonmotor features. The recognition of early features that predate classic motor symptoms will be important as effective neuroprotective therapy becomes available. Later-stage features often contribute markedly to disability and impaired quality of life and, therefore, represent an important future therapeutic challenge.

Fox SH, Brotchie JM, Lang AE. · Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, ON, Canada. · Lancet Neurol. · Pubmed #18848312 No free full text.

Abstract: Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.

Fox SH, Lang AE. · Division of Neurology, Toronto Western Hospital, Movement Disorders Clinic, University of Toronto, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #18781677 No free full text.

Abstract: Long term levodopa therapy in Parkinson's disease (PD) results in a range of problems. These include fluctuations in FD symptoms termed motor fluctuations, as well as non-motor symptoms, termed non-motor fluctuations. Here we review the phenomenology and methods of assessing these levodopa-related complications.

Litvan I, Chesselet MF, Gasser T, Di Monte DA, Parker D, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17483689 No free full text.

Abstract: We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors. Although there is extensive new information on the etiology and pathogenesis of PD, which may advance its treatment, new syntheses of this information are needed. The second part of this two-part, state-of-the-art review by leaders in PD research critically examines the research field to identify areas for which new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part II are genetics, animal models, and oxidative stress.

Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D, Price DL. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17413315 No free full text.

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Moro E, Lang AE. · University of Toronto, Department of Medicine, Movement Disorders Center, 399 Bathurst Street, McL7 402, Canada. · Expert Rev Neurother. · Pubmed #17144783 No free full text.

Abstract: Deep-brain stimulation is currently the most effective surgical treatment for advanced Parkinson's disease. The relevant targets to date are the subthalamic nucleus and the globus pallidus internus, although the thalamus (ventralis intermedius nucleus) is preferred in tremor-dominant, aged Parkinson's disease patients. Long-term benefit in cardinal parkinsonian signs, motor fluctuations and dyskinesia has been reported in 5-year follow-up studies of subthalamic nucleus deep-brain stimulation. However, some psychiatric consequences have raised important issues and emphasized the need for an experienced deep-brain stimulation surgical team. This team should be multidisciplinary and involve movement disorder neurologists, neurosurgeons, neuropsychologists and psychiatrists. The recent observation that deep-brain stimulation of the pedunculopontine nucleus improves axial signs, possibly even in those less responsive to levodopa, brings new hope to the management of advanced Parkinson's disease.

Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE, Deuschl G. · Parkinson's Disease Research Education and Clinical Center, Philadelphia VA Hospital, Philadelphia, Pennsylvania 19104, USA. · Mov Disord. · Pubmed #16892449 No free full text.

Abstract: Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Voon V, Moro E, Saint-Cyr JA, Lozano AM, Lang AE. · Department of Psychiatry, Toronto Western Hospital, UHN, Toronto, Canada. · Adv Neurol. · Pubmed #16383217 No free full text.

Abstract: Bilateral subthalamic stimulation is a very effective neurosurgical treatment for advanced Parkinson's disease. Despite the range and frequency of psychiatric symptoms occurring in the postoperative state, most of these symptoms are transient and manageable. In clinical practice, preoperative psychiatric vulnerability, as with that of preoperative cognitive status, takes on an important role. Psychiatric assessment and active preoperative and postoperative intervention can potentially modify psychiatric outcomes. These psychiatric and psychological issues will take on greater importance, particularly with the rapid expansion of the number of neurosurgical sites and the need for adequate assessment and optimal management of patients. The paucity of the literature underscores the need for well-designed studies on psychiatric issues investigating both pathophysiology and clinical outcomes.

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.

Zadikoff C, Lang AE. · Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · Brain. · Pubmed #15930045 links to  free full text

Abstract: The definition of apraxia specifies that the disturbance of performed skilled movements cannot be explained by the more elemental motor disorders typical of patients with movement disorders. Generally this does not present a significant diagnostic problem when dealing with 'higher-level' praxic disturbances (e.g. ideational apraxia), but it can be a major confound in establishing the presence of limb-kinetic apraxia. Most motor disturbances characteristic of extrapyramidal disorders, particularly bradykinesia and dystonia, will compromise the ability to establish the presence of loss of dexterity and deftness that constitutes this subtype. The term 'apraxia' has also been applied to other motor disturbances, such as 'gait apraxia' and 'apraxia of eyelid opening', that perhaps are misnomers, demonstrating the lack of a coherent nomenclature in this field. Apraxia is a hallmark of corticobasal degeneration (CBD) and historically this has received the most attention among the movement disorders. Corticobasal degeneration is characterized by various forms of apraxia affecting limb function, particularly ideomotor apraxia and limb-kinetic apraxia, although buccofacial and oculomotor apraxia can be present as well. The syndrome of parkinsonism and prominent apraxia, designated the 'corticobasal syndrome' (CBS), may be caused by a variety of other central nervous system pathologies including progressive supranuclear palsy (PSP), Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementias. Distinct from the CBS, PSP and Parkinson's disease can demonstrate varying degrees of apraxia on selected tests, especially in those patients with more severe cognitive dysfunction. Diseases that cause the combination of apraxia and a primary movement disorder most often involve a variety of cerebral cortical sites as well as basal ganglia structures. Clinical-pathological correlates and functional imaging studies are compromised by both this diffuse involvement and the confusion experienced in the clinical evaluation of apraxia in the face of the additional elemental movement disorders. Finally, although apraxia results in clear disability in patients with the CBS, it is not clear how milder ideomotor apraxia found on specific testing contributes to patients' overall day-to-day motor disability.

Marras C, Lang AE. · Toronto Western Hospital, Movement Disorders Centre, 7 McLaughlin, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. · Expert Rev Neurother. · Pubmed #15853525 No free full text.

Abstract: Three areas of intense investigation in Parkinson's disease clinical trials include symptomatic treatment of Parkinsonism, disease-modifying therapy (or neuroprotection), and the prevention and treatment of motor complications of dopaminergic therapy. Difficulty interpreting the results of many studies in recent years has been attributed to problems with the chosen outcome measures. This article reviews the most common outcome measures used, assesses their positive attributes and proposes needs for future research. The Unified Parkinson's disease Rating Scale has been extensively validated and is by far the most common outcome measure used in trials of symptomatic therapy. Ambiguities in the response scale descriptors, poor inter-rater reliability of some items and a lack of items addressing nonmotor features of the disease are being addressed in a revision of the scale. Quality of life outcomes are being used in the minority of clinical trials, and no single generic or disease-specific quality of life measure is being used most frequently. Additional work validating several of the disease-specific instruments is needed. When a generic measure is used, its validity for use in Parkinson's disease must be critically assessed despite its previously established validity in other diseases. With respect to measuring motor complications, significant unmet needs include a consensus as to the best way to define the first motor complication and validating time to the first occurrence of motor complications as a surrogate of future disability and quality of life. Measuring the effectiveness of a potential neuroprotective agent presents unique challenges, particularly since symptomatic effects of the experimental agent or concomitant treatment can obscure any neuroprotective effects. Study designs and biomarkers are being developed that may overcome this problem. Currently, neuroimaging techniques that reflect function of the dopaminergic system are the most promising biomarkers but still require additional validation.

Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, Meija-Santana H, Vieregge P, Jacobs H, Bressman SB, Lang AE, Kann M, Abbruzzese G, Martinelli P, Schwinger E, Ozelius LJ, Pramstaller PP, Klein C, Kramer P. · Department of Neurology, University of Lübeck, Lübeck, Germany. · Mov Disord. · Pubmed #15390068 No free full text.

Abstract: Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.

Postuma RB, Lang AE. · Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, Ontario, Canada. · Neurology. · Pubmed #15365141 No free full text.

Abstract: Epidemiologic evidence has linked elevation of serum homocysteine to an increased risk of coronary artery disease, stroke, and dementia. An increase in homocysteine levels in Parkinson disease (PD) recently has been discovered. Although B vitamin status and genetic factors are important modifying influences determining the degree of this elevation, the main cause appears to be therapy with L-dopa. It has been suggested that breakdown of L-dopa by catechol-O-methyltransferase results in increased homocysteine formation. Therefore, there are reasons to suggest that management of PD may render patients at increased risk of stroke, heart disease, dementia, and even accelerated nigral degeneration. At present, no controlled prospective studies have evaluated this phenomenon, although they are ongoing.

Lang AE, Obeso JA. · Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · Lancet Neurol. · Pubmed #15099546 No free full text.

Abstract: Levodopa remains the most effective treatment for Parkinson's disease (PD). However, the drug is complicated by a wide range of adverse effects, most notably motor fluctuations and dyskinesias. Long-acting dopamine agonists are associated with a reduced incidence of these complications and modern surgical approaches and pharmacological methods of providing more continuous dopaminergic stimulation have a substantial ameliorative effect on these problems. Despite these advances, disease progression remains unaffected. For this reason there has been much enthusiasm for cellular therapies designed to replace degenerating nigrostriatal dopaminergic neurons. However, recent fetal transplant trials have failed to show expected benefit and have been complicated by medication dyskinesias". Even if successful, such treatment may be predestined to provide no better outcome than available treatments given current medical and surgical experience that emphasises the increasingly critical role of "non-dopaminergic" symptoms to quality of life in late-stage PD. Knowledge of the widespread, multisystem nature of the neurodegeneration that accounts for these problems suggests that restoration of the nigrostriatal dopamine system should not be the ultimate goal of future research.

Gálvez-Jiménez N, Lang AE. · Department of Neurology, The Cleveland Clinic-Florida, Weston (Fort Lauderdale), FL 3331, USA. · Neurol Clin. · Pubmed #15062517 No free full text.

Abstract: The perioperative management of patients who have PD requires knowledge of the potential complications of various types of surgery. Neurologists should be able to balance patient comfort against the potential complications of antiparkinsonian therapy. The authors believe that the approach outlined in the Appendix increases patient comfort, facilitates nursing care, and can potentially reduce some of the complications seen in the postoperative period.

Marras C, Rochon P, Lang AE. · Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada. · Arch Neurol. · Pubmed #12433259 links to  free full text

Abstract: CONTEXT: The clinical course of Parkinson disease (PD) varies from patient to patient. A number of studies investigating predictors of prognosis in patients with PD have been performed. OBJECTIVE: To summarize evidence on predicting the rate of motor decline and increasing disability in early PD. DATA SOURCES: English-language and French-language literature cited in the MEDLINE database (1966-2002). STUDY SELECTION: Cohort and case-control studies investigating associations between clinical features and subsequent motor impairment or disability were selected. DATA EXTRACTION: Study methods and results were abstracted by a single reviewer. DATA SYNTHESIS: The results of 13 studies were summarized qualitatively. Study methods were highly variable, particularly regarding the choice of outcome measure. Baseline motor impairment and cognitive impairment are probable predictors of more rapid motor decline and disability. A lack of tremor at onset and older age both appear to be predictive of increasing disability, but conflicting results exist for their association with the rate of change of motor impairment. Family history of PD does not appear to be prognostically important. The prognostic value of many other factors studied is uncertain owing to conflicting or unconfirmed results. CONCLUSIONS: Uncertainty remains about the prognostic importance of many baseline clinical features in PD. Greater baseline impairment, early cognitive disturbance, older age, and lack of tremor at onset appear to be adverse prognostic factors.

Shafiq M, Lang AE. · Department of Medicine (Neurology), Toronto Western Hospital, Toronto, Ontario, Canada. · Adv Neurol. · Pubmed #11968474 No free full text.

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Lang AE, Widner H. · Division of Neurology, Toronto Western Hospital Movement and University of Toronto, Ontario, Canada. · Mov Disord. · Pubmed #11948762 No free full text.

Abstract: Critical to the successful application of deep brain stimulation for the treatment Parkinson's disease is the proper selection of patients who will reliably benefit from this procedure and the successful evaluation of the responses obtained. This review will discuss the various factors influencing patient selection and summarize the recommended approach to patient assessment by using the Core Assessment Program for Surgical Interventions and Transplantation in Parkinson's Disease (CAPSIT-PD).

Lozano AM, Lang AE. · Division of Neurosurgery, Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada. · Adv Neurol. · Pubmed #11554004 No free full text.

This publication has no abstract.