Saturday, 21 January 2012

Drug-Induced Parkinsonism in the Elderly: Incidence, Management and Prevention

Drugs Aging. 2012 Jan 17. [Epub ahead of print]
López-Sendón JL, Mena MA, García de Yébenes J.


Department of Neurology, Hospital Ramn y Cajal, Madrid, Spain.


Drug-induced parkinsonism (DIP) has been claimed to be the most prevalent cause of secondary parkinsonism in clinical practice in the Western world. Since the first descriptions in the early 1950s the prevalence of DIP seems to be increasing and approaching that of idiopathic Parkinson's disease (iPD) due to the aging of the population and the rising of polypharmacotherapy. Despite the wide interest this subject has raised in the past, it seems to be frequently overlooked by the medical community. It is particularly burdensome for the elderly and its management includes recognition of symptoms and identification of risk factors and offending agents. Prompt discontinuation of the causative agent leads to a marked improvement, although the condition might persist or remit slowly in up to 10% of the patients. Risk factors for developing DIP include older age; female sex; cognitive impairment; potency, dose and length of treatment; pre-existing extrapyramidal signs; and, very likely, a background of inherited predisposition. The main causative agents are dopamine receptor antagonists but the list of drugs without such a well known and straightforward mechanism of action is large. All antipsychotics, including atypicals (except clozapine) may produce parkinsonism. Although many drugs cause parkinsonism in a dose-related manner, there is an enormous variation in individual susceptibility. The clinical syndrome is less likely to produce tremor than iPD, and is more likely to be symmetrical, but the two syndromes might not be distinguished in any individual patient. Functional neuroimaging tests, which use ligands that bind to the dopamine transporter, are useful for distinguishing iPD from DIP in doubtful cases in patients treated with antipsychotics. The estimated presynaptic dopamine secreting neurons should be diminished in iPD but normal in DIP produced by dopamine receptor blockers, as assessed by molecular imaging techniques evaluating striatal dopamine transporters (DATs). Prompt recognition and discontinuation of the culprit are the keys to the management of DIP. In persistent cases, specific therapies including anticholinergics and amantadine may provide symptomatic relief. Levodopa and dopamine receptor agonists might be an option in selected cases in which dopamine nerve terminal defects are present. The weight and scope of DIP varies with the age and underlying health of the patient, imposing a significant burden on the elderly who, in many cases, experience significant functional deterioration that leads to hospitalization and has vast economic consequences. This article reviews the epidemiology, pathogenic mechanisms, implicated drugs, clinical features and management of DIP and highlights the need for increased awareness of this iatrogenic condition.

Towards remote evaluation of movement disorders via smartphones

Conf Proc IEEE Eng Med Biol Soc. 2011 Aug;2011:5240-3.
Kostikis N, Hristu-Varsakelis D, Arnaoutoglou M, Kotsavasiloglou C, Baloyiannis S.


Recent advances in mobile phone technology have placed an impressive array of sensing and communication equipment at the hands of an ever-growing number of people. One of the areas which can potentially be transformed by the availability of what is essentially a cheap, ubiquitous networked sensor, is that of remote diagnosis of movement disorders, such as Parkinson's disease. This work describes a smartphone-based method for detecting and quantifying the hand tremor associated with movement disorders using signals from the accelerometer and gyroscope embedded in the patient's phone. Our approach is web-based and user-friendly, requiring minimal user interaction. In clinical experiments with twenty subjects, we found that by combining both accelerometer and gyroscope signals, we were able to correctly identify those with hand tremor, using very simple signal metrics.

"On" state freezing of gait in Parkinson disease: A paradoxical levodopa-induced complication

Neurology. 2012 Jan 18. [Epub ahead of print]
Espay AJ, Fasano A, van Nuenen BF, Payne MM, Snijders AH, Bloem BR.



To describe the phenotype of levodopa-induced "on" freezing of gait (FOG) in Parkinson disease (PD).


We present a diagnostic approach to separate "on" FOG (deterioration during the "on state") from other FOG forms. Four patients with PD with suspected "on" FOG were examined in the "off state" (>12 hours after last medication intake), "on state" (peak effect of usual medication), and "supra-on" state (after intake of at least twice the usual dose).


Patients showed clear "on" FOG, which worsened in a dose-dependent fashion from the "on" to the "supra-on" state. Two patients also demonstrated FOG during the "off state," of lesser magnitude than during "on." In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating "off" FOG.


True "on" FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating "off" FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states.

Thursday, 19 January 2012

NHS facing neurology time bomb

BBC News Item

This news item on the BBC website details how research leaders in neurology are encouraging the government to recognise the ever increasing burden of neurological diseases including Parkinson's.

Treatment for Helicobacter pylori infection and risk of parkinson's disease in Denmark.

J Neurol. 2012 Jan 17. doi: 10.1111/j.1468-1331.2011.03643.x. [Epub ahead of print]

Nielsen HH, Qiu J, Friis S, Wermuth L, Ritz B.


Background and purpose:  It has been speculated that gastrointestinal infection with Helicobacter pylori (HP) contributes to the development of Parkinson's disease (PD). We used nationwide Danish registers to investigate this hypothesis. Methods:  We identified 4484 patients with a first time PD diagnosis between 2001 and 2008 from the Danish National Patient Register (DNPR) and 22 416 population controls from the Danish Civil Registration System (CRS). Information on drug use was obtained from the National Prescription Registry (NPR). We used logistic regression to compute odds ratios (OR) for the association between treatment for HP and risk of PD. Results:  Prescriptions for HP-eradication drugs and proton pump inhibitors (PPI) 5 or more years prior to the diagnosis of PD were associated with a 45% and 23% increase in PD risk, respectively. Hospitalizations and outpatient visits for gastritis and peptic/duodenal ulcers, however, were not associated with PD. Conclusions:  Our population-based study suggests that chronic HP infections and/or gastritis contribute to PD or that these are PD-related pathologies that precede motor symptoms.

Wednesday, 18 January 2012

Psychosis, apathy, depression and anxiety in Parkinson's disease.

Gallagher D, Schrag A

Neurobiol. Dis. 2012 Jan 3. [Epub ahead of print]

Psychiatric symptoms are important non-motor features in PD, which occur at high frequency and have significant impact on health related quality of life. This review concentrates on the prevalence, pathophysiology, diagnosis and treatment of depression, anxiety, apathy and psychosis. The pathophysiology of these disorders is complex, reflecting the widespread brainstem and cortical pathology in PD, with involvement of several neurotransmitters, including dopaminergic, serotonergic, noradrenergic and cholinergic systems. The diagnosis of psychiatric conditions, in particular affective disorders, is challenging because of the overlap of somatic features of psychiatric disorders and underlying movement disorder. The pathogenesis is likely to differ considerably from non-PD patients, and treatments used in general psychiatry services may not be as effective in PD and will require clearer clarification in well-designed clinical studies. Management strategies include adjustment of dopaminergic medication, use of psychotropic treatments and behavioural and psychological approaches. However, the future challenge will be to develop treatments developed specifically for the pathogenesis of PD.

Friday, 13 January 2012

Progression of motor symptoms in Parkinson's disease.

Neurosci Bull. 2012 Feb;28(1):39-48.

Xia R, Mao ZH.


Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have different rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.

Tuesday, 10 January 2012

Clinical Trial: Nicotine Patch Shows Benefits in Mild Cognitive Impairment

ST. PAUL, Minn. – Using a nicotine patch may help improve mild memory loss in older adults, according to a study published in the January 10, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology.

Nicotine has been shown to improve cognitive performance in smokers who have stopped smoking and previous short-term studies with nicotine have shown attention and memory improvement in people with Alzheimer’s disease. This study looked at nicotine in people with mild cognitive impairment, which is the stage between normal aging and dementia when people have mild memory or thinking problems but no significant disability.

The study involved 74 people with an average age of 76 who had mild cognitive impairment and were not smokers. Half of the participants received a nicotine patch of 15 mg per day for six months and half received a placebo. The participants took several tests of memory and thinking skills at the start of the study and again after three and six months.

After six months of treatment, the nicotine-treated group regained 46 percent of normal performance for age on long-term memory, whereas the placebo group worsened by 26 percent over the same time period.

“People with mild memory loss should not start smoking or using nicotine patches by themselves, because there are harmful effects of smoking and a medication such as nicotine should only be used with a doctor's supervision,” said study author Paul Newhouse, MD, of Vanderbilt University School of Medicine in Nashville. “But this study provides strong justification for further research into the use of nicotine for people with early signs of memory loss. We do not know whether benefits persist over long periods of time and provide meaningful improvement.”

There were no serious side effects for the people receiving the nicotine patch.

Nicotine stimulates receptors in the brain that are important for thinking and memory skills. People with Alzheimer’s disease lose some of these receptors.

The study was supported by the National Institute on Aging and the National Institute of General Medical Sciences. Pfizer Inc. provided the transdermal nicotine patches.

Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers

  1. Neurology January 3, 2012vol. 78 no. 1 55-61
  1. J.O. Aasly, MD, PhD*
  2. M. Shi, PhD*
  3. V. Sossi, PhD
  4. T. Stewart, PhD
  5. K.K. Johansen, MD,
  6. Z.K. Wszolek, MD
  7. R.J. Uitti, MD
  8. K. Hasegawa, MD, PhD
  9. T. Yokoyama, MD, PhD,
  10. C.P. Zabetian, MD
  11. H.M. Kim, MD
  12. J.B. Leverenz, MD
  13. C. Ginghina, MD
  14. J. Armaly, BS,
  15. K.L. Edwards, PhD
  16. K.W. Snapinn, MS
  17. A.J. Stoessl, MD, FRCPC and 
  18. J. Zhang, MD, PhD
  1. From the Department of Neurology (J.O.A., K.K.J.), St Olav's University Hospital, Trondheim; Department of Neuroscience (J.O.A., K.K.J.), Norwegian University of Science and Technology, Trondheim, Norway; Departments of Pathology (M.S., T.S., C.G., J.A., J.Z.), Neurology (C.P.Z., H.M.K., J.B.L.), and Psychiatry and Behavioral Sciences (J.B.L.), University of Washington School of Medicine, Seattle; Department of Physics & Astronomy (V.S.), University of British Columbia, Vancouver Hospital and Health Sciences Centre, Purdy Pavilion, Vancouver, Canada; Department of Neurology (Z.K.W., R.J.U.), Mayo Clinic Florida, Jacksonville; Department of Neurology (K.H., T.Y.), National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan; Geriatric Research, Education, and Clinical Center (C.P.Z.), Parkinson's Disease Research, Education, and Clinical Center (C.P.Z., H.M.K., J.B.L.), and Mental Illness Research, Education, and Clinical Center (J.B.L.), Veterans Affairs Puget Sound Health Care System, Seattle, WA; Department of Epidemiology (K.L.E., K.W.S.), University of Washington School of Public Health, Seattle; and Pacific Parkinson's Research Centre (A.J.S.), University of British Columbia & Vancouver Coastal Health, 

Objective: The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.

Methods: CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-L-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.

Results: Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most commonLRRK2 variant in our cohort, significant correlations were also observed for tau.

Conclusions: The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

Monday, 2 January 2012

Risk of Cardiac Valve Regurgitation with Dopamine Agonist use in Parkinson's Disease and Hyperprolactinaemia: A Multi-Country, Nested Case-Control Study

Drug Saf. 2011 Dec 29. [Epub ahead of print]
Trifirò G, Mokhles MM, Dieleman JP, van Soest EM, Verhamme K, Mazzaglia G, Herings R, de Luise C, Ross D, Brusselle G, Colao A, Haverkamp W, Schade R, van Camp G, Zanettini R, Sturkenboom MC.


Background: There is growing evidence that ergot dopamine agonists may induce cardiac valve regurgitation (CVR) in persons with Parkinson's disease. It is unclear whether the CVR risk is increased with ergot-dopamine agonist use in persons with hyperprolactinaemia, in whom the dose is much lower. Objective: The aim of the study was to explore the association between different dopamine agonists and CVR in patients with Parkinson's disease or hyperprolactinaemia. Design: Nested case-control studies conducted separately in cohorts of Parkinson's disease and hyperprolactinaemia patients. Cases were patients who developed newly diagnosed CVR. Controls were CVR-free patients from the same cohorts and were matched to cases by age, sex, database and calendar year. Setting and Patients: Study patients were identified from over 4.5 million persons in The Health Improvement Network (THIN; UK), Health Search (Italy), and Integrated Primary Care Information (IPCI; the Netherlands) general practice databases in the years 1996-2007. The Parkinson's disease cohort included new users of dopamine agonists or levodopa, while the hyperprolactinaemia cohort included new users or non-users of dopamine agonists. Main Outcome Measure: Risk of newly diagnosed CVR with dopamine agonist use compared with levodopa use in the Parkinson's disease cohort, and dopamine agonist-naïve patients in the hyperprolactinaemia cohort. Results: In the Parkinson's disease cohort (7893 dopamine agonist users, 11 766 levodopa users), 85 incident CVR cases were identified. Increased CVR risk was observed for ergot dopamine agonists (adjusted OR [OR(adj)] 3.82; 95% CI 2.14, 6.81), but not for non-ergot dopamine agonists (OR(adj) 1.20; 95% CI 0.63, 2.29). In the hyperprolactinaemia cohort (6740 dopamine agonist users and 14 299 dopamine agonist-naïve patients), 37 CVR cases were identified during a mean follow-up of 4.5 years and 3.5 years for new users and non-users of dopamine agonists, respectively. However, no association with ever use of ergot dopamine agonists was observed (OR(adj) 0.47; 95% CI 0.20, 1.19). Conclusion: Ergot-derived dopamine agonists are associated with an increased risk of CVR in Parkinson's disease but not in hyperprolactinaemia patients.

Subsequent Risks of Parkinson Disease in Patients with Autoimmune and Related Disorders: A Nationwide Epidemiological Study from Sweden

Neurodegener Dis. 2011 Dec 23. [Epub ahead of print]
Li X, Sundquist J, Sundquist K.


Objectives: To investigate associations between autoimmune disorders and Parkinson disease (PD), and to study whether the risk is associated with follow-up time and age. Methods: Standardized incidence ratios (SIRs) were calculated for PD in patients with autoimmune disorders by comparing them to subjects without autoimmune disorders. Results: Among 310,522 patients with a total of 33 conditions of autoimmune disorders, 932 patients developed subsequent PD, giving an overall SIR of 1.33 and 1.19 for PD diagnosed later than 1 year after follow-up. Six types of autoimmune disorders showed an increased risk. These conditions included: amyotrophic lateral sclerosis, Graves's disease/hyperthyroidism, Hashimoto's disease/hypothyroidism, multiple sclerosis, pernicious anemia, and polymyalgia rheumatica. The risks depended on the age at hospitalization for PD. Conclusions: A 33% overall excess risk of PD was noted among patients with an autoimmune disorder; the risk was increased during the first 10 years of follow-up after hospitalization of autoimmune disorders.

Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2),...