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1.  Perioperative Atrial Fibrillation and the Long-term Risk of Ischemic Stroke 
JAMA  2014;312(6):616-622.
Clinically apparent atrial fibrillation increases the risk of ischemic stroke. In contrast, perioperative atrial fibrillation may be viewed as a transient response to physiological stress, and the long-term risk of stroke after perioperative atrial fibrillation is unclear.
To examine the association between perioperative atrial fibrillation and the long-term risk of stroke.
Retrospective cohort study using administrative claims data on patients hospitalized for surgery (as defined by surgical diagnosis related group codes), and discharged alive and free of documented cerebrovascular disease or preexisting atrial fibrillation from nonfederal California acute care hospitals between 2007 and 2011. Patients undergoing cardiac vs other types of surgery were analyzed separately.
Previously validated diagnosis codes were used to identify ischemic strokes after discharge from the index hospitalization for surgery. The primary predictor variable was atrial fibrillation newly diagnosed during the index hospitalization, as defined by previously validated present-on-admission codes. Patients were censored at postdischarge emergency department encounters or hospitalizations with a recorded diagnosis of atrial fibrillation.
Of 1 729 360 eligible patients, 24 711 (1.43%; 95% CI, 1.41%–1.45%) had new-onset perioperative atrial fibrillation during the index hospitalization and 13 952 (0.81%; 95% CI, 0.79%–0.82%) experienced a stroke after discharge. In a Cox proportional hazards analysis accounting for potential confounders, perioperative atrial fibrillation was associated with subsequent stroke both after noncardiac and cardiac surgery. Type of SurgeryCumulative Rate of Stroke 1 Year AfterHospitalization, % (95% CI)Hazard Ratio (95% CI)PerioperativeAtrial FibrillationNo PerioperativeAtrial FibrillationNoncardiac1.47 (1.24–1.75)0.36 (0.35–0.37)2.0 (1.7–2.3)Cardiac0.99 (0.81–1.20)0.83 (0.76–0.91)1.3 (1.1–1.6) The association with stroke was significantly stronger for perioperative atrial fibrillation after noncardiac vs cardiac surgery (P < .001 for interaction).
Among patients hospitalized for surgery, perioperative atrial fibrillation was associated with an increased long-term risk of ischemic stroke, especially following noncardiac surgery.
PMCID: PMC4277813  PMID: 25117130
2.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
PMCID: PMC4055488  PMID: 24922517
3.  A Pilot Study Evaluating the Contribution of SLC19A1 (RFC-1) 80G>A Polymorphism to Alzheimer's Disease in Italian Caucasians 
BioMed Research International  2014;2014:608104.
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. Polymorphisms of genes involved in folate metabolism have been frequently suggested as risk factors for sporadic AD. A common c.80G>A polymorphism (rs1051266) in the gene coding for the reduced folate carrier (SLC19A1 gene, commonly known as RFC-1 gene) was investigated as AD risk factor in Asian populations, yielding conflicting results. We screened a Caucasian population of Italian origin composed of 192 sporadic AD patients and 186 healthy matched controls, for the presence of the RFC-1 c.80G>A polymorphism, and searched for correlation with circulating levels of folate, homocysteine, and vitamin B12. No difference in the distribution of allele and genotype frequencies was observed between AD patients and controls. No correlation was observed among the genotypes generated by the RFC-1 c.80G>A polymorphism and circulating levels of folate, homocysteine, and vitamin B12 either in the whole cohort of subjects or after stratification into clinical subtypes. Present results do not support a role for the RFC-1 c.80G>A polymorphism as independent risk factor for sporadic AD in Italian Caucasians.
PMCID: PMC4068058  PMID: 24995314
4.  Psychometric properties of the Italian version of the Scales for Outcomes in Parkinson’s disease-Cognition (SCOPA-Cog) 
Functional Neurology  2013;28(2):121-125.
The Scales for Outcomes in Parkinson’s disease-Cognition (SCOPA-Cog) has been shown to be a clinimetrically rigorous and valid instrument for a disease-oriented neuropsychological assessment of Parkinson’s disease (PD) patients. In the present study we evaluated the psychometric properties of the Italian version of the SCOPA-Cog in 121 PD patients. The scale explores memory, attention, and executive and visuospatial functions and takes approximately 20 minutes to administer. Data distribution (skewness= −0.23) and internal consistency (Cronbach’s alpha= 0.78) were satisfactory. Standard error of measurement was 3.42. The outcome was significantly worse in patients with an abnormal score on the Dementia Rating Scale (DRS) (SCOPACog mean score 14.6±5.1 out of a total of 43) with respect to cognitively intact subjects (24.2±4.3) (p<0.0001). The DRS showed good convergent validity (Spearman rho= 0.77, p<0.0001), and a high coefficient of variation (= 0.34). These findings support the goodness of the Italian SCOPA-Cog in terms of metrics and validity.
PMCID: PMC3812729  PMID: 24125562
dementia; Parkinson’s disease; SCOPA-Cog
5.  Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry 
PLoS ONE  2013;8(7):e68279.
Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices.
PMCID: PMC3706610  PMID: 23874570
6.  Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson’s disease: a review 
The spatiotemporal progression of dopamine depletion in Parkinson’s disease (PD) provides a special model for assessing dopaminergic effects on neural systems with differential baseline dopamine levels. This study aims at reviewing cognitive effects of dopaminergic stimulation in PD. While considering dopaminergic drugs (levodopa or dopamine agonists), temporal intervals (acute or chronic) and cognitive domains, we found that empirical evidence was almost focused on acute effects of levodopa on executive functions. The paucity of empirical evidence suggests that no meaningful conclusions can be actually drawn and further research is needed in relation to: (1) other cognitive domains; (2) the acute cognitive effects of dopamine agonists, as compared with levodopa; (3) possible differences between cognitive effects of different dopamine agonists; (4) the cognitive effects of chronic dopaminergic therapies. The latter issue is of particular clinical interest considering that many PD patients present a mild cognitive impairment: is this cognitive feature worsened or improved by the prolonged dopaminergic therapy? In addition to the potential risk of inducing dyskinesia and behavioral side effects such as impulse control disorders, also cognitive effects of prolonged dopaminergic treatments should be taken in account by clinicians in order to anticipate or to delay their prescription to PD patients.
PMCID: PMC3805397  PMID: 24167681
acute cognitive effect; chronic cognitive effect; cognition; dopamine agonists; executive functions; levodopa; Parkinson’s disease
7.  Continuous intestinal infusion of levodopa/carbidopa in advanced Parkinson’s disease: efficacy, safety and patient selection 
Functional Neurology  2013;27(3):147-154.
Long-term oral therapy with levodopa is associated with the development of motor fluctuations and dyskinesia in a large percentage of patients with Parkinson’s disease (PD). Motor complications are associated with a number of non-motor symptoms and have a negative impact on disability and quality of life. There are three therapeutic options available for the management of patients at this advanced stage: high frequency deep brain stimulation, continuous subcutaneous infusion of apomorphine, and continuous intestinal infusion of levodopa/carbidopa. On the basis of published data and in consideration of the risk-benefit profile of current therapeutic strategies, we here propose an algorithm to help clinicians select the most suitable treatment option for patients with advanced PD.
PMCID: PMC3812765  PMID: 23402675
continuous dopaminergic stimulation; deep brain stimulation; levodopa/carbidopa intestinal gel infusion; Parkinson’s disease; patient selection
8.  The Epidemiology and Clinical Manifestations of Dysexecutive Syndrome in Parkinson’s Disease 
This mini-review summarizes the evidence of the cognitive and behavioral features of dysexecutive syndrome in Parkinson’s disease (PD). Deficits in response inhibition, set-shifting, mental flexibility, and strategy have been frequently described from the earliest stages of PD, although there are inconsistencies in study findings due to the complexity of the executive function (EF) construct and methodological limitations. Behavioral disorders of PD, e.g., apathy, distractibility, perseverative behavior, and impulse-control disorders, may be viewed as the other side of dysexecutive syndrome. Despite the interrelationship between the cognitive and behavioral domains, some reports reveal that the two syndromes may be dissociated, suggesting that both aspects must be clinically assessed. EFs are widely associated with the prefrontal areas, although dysexecutive syndrome may be observed in patients with damage to other brain regions. EFs drive numerous abilities essential to daily life, such as prospective remembering and language comprehension, which may be impaired in PD subjects. Considering the impact of dysexecutive syndrome on independence and quality of life, early detection of executive impairment is crucial in the management of PD.
PMCID: PMC3497716  PMID: 23162529
Parkinson’s disease; dysexecutive syndrome; executive function; neuropsychological test; cognitive impairment
9.  IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients 
Autism Research and Treatment  2012;2012:679801.
Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3) IGF1, cross the blood brain barrier, and (1–3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.
PMCID: PMC3420537  PMID: 22934177
10.  A molecular signature in blood identifies early Parkinson’s disease 
The search for biomarkers in Parkinson’s disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD.
The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60–0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08–1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75–0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60–0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14–1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96.
The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer’s disease (n = 29).
The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.
PMCID: PMC3424147  PMID: 22651796
Alzheimer’s disease; Sporadic Parkinson’s disease; Blood Biomarker; CSF Biomarkers; E3 ubiquitin ligase; SCF; SKP1; Heat shock protein Hsc-70; Early diagnosis
11.  Alexithymia may modulate decision making in patients with de novo Parkinson’s disease  
Functional Neurology  2011;26(3): 127 - 131 .
The aim of this study was to investigate whether and how alexithymia may influence decision making under conditions of uncertainty, assessed using the Iowa Gambling Task, in patients with newly diagnosed, untreated (de novo) Parkinson’s disease, as previously reported for healthy subjects.
Twenty-four patients with de novo Parkinson’s disease underwent a neuropsychological and neuropsychiatric assessment, including the Toronto Alexithymia Scale, the Geriatric Depression Scale Short Form, and the Iowa Gambling Task (IGT).
The assessment showed that 12 patients were alexithymic and 12 were non-alexithymic; seven patients were found to be mildly depressed and 17 non-depressed. Alexithymic and non-alexithymic patients did not differ in the IGT total score; however, significant differences emerged across the third block of the IGT, in which the alexithymic patients outperformed the nonalexithymic patients. Depression did not influence IGT performance.
Alexithymia may modulate decision making, as assessed with the IGT; alexithymia could be associated with faster learning to avoid risky choices and negative feedback, as previously reported in some studies conducted in anxious or depressed patients.
PMCID: PMC3814549  PMID: 22152433
alexithymia ;  anxiety ;  decision making ;  de novo Parkinson’s disease ;  depression ;  Iowa Gambling Task
12.  Dopamine Transporter SPECT Imaging in Corticobasal Syndrome 
PLoS ONE  2011;6(5):e18301.
To investigate dopaminergic function in a large cohort of patients with corticobasal syndrome (CBS) and describe its relationship with clinical features in comparison to Parkinson's disease and healthy control subjects. In addition, we assessed prevalence and features of individuals with CBS and in vivo evidence of preserved nigral neuronal density.
Substantia nigra pars compacta (SNc) neuronal degeneration is a mandatory pathological criterion for definite corticobasal degeneration, though sporadic autopsy-proven cases with ante-mortem imaging evidence of preserved nigral terminals have been recently described.
In this multicenter study, we investigated presynaptic nigrostriatal function in 36 outpatients fulfilling clinical criteria for “probable corticobasal degeneration” (age 71±7.3 years; disease duration 3.9±1.6 years), 37 PD and 24 healthy control subjects using FP-CIT single photon emission computed tomography. Clinical, neuropsychological, and magnetic resonance imaging assessment was performed to characterize CBS patients. Linear discriminant analysis was used to categorize normal vs. pathological scans.
FP-CIT binding reduction in patients with CBS was characterized by larger variability, more uniform reduction throughout the striatum and greater hemispheric asymmetry compared to PD. Moreover, there was no significant correlation between tracer uptake values and clinical features such as disease duration and severity. Despite all CBS subjects showed obvious bilateral extrapyramidal signs, FP-CIT uptake was found to be normal bilaterally in four CBS patients and only unilaterally in other four cases. Extensive clinical, neuropsychological and imaging assessment did not reveal remarkable differences between CBS subjects with normal vs. pathological FP-CIT uptake.
Our findings support the hypothesis that extrapyramidal motor symptoms in CBS are not invariably associated with SNc neuronal degeneration and that supranigral factors may play a major role in several cases. CBS individuals with normal FP-CIT uptake do not show any clinical or cognitive feature suggesting a different pathology than CBD.
PMCID: PMC3085517  PMID: 21559307
13.  Cerebellar Ataxia with Complete Clinical Recovery and Resolution of MRI Lesions Related to Central Pontine Myelinolysis: Case Report and Literature Review 
Case Reports in Neurology  2010;2(3):157-162.
There are several reports of central pontine myelinolysis (CPM) in a setting of malnutrition, alcoholism, and chronic debilitating illness associated with electrolyte abnormalities, especially hyponatremia. The cause of myelinolysis is still under debate, and, although osmotic effects are thought to be responsible in most cases, alternative pathological factors should be considered [King et al.: Am J Med Sci 2010;339:561–567]. We report a case of CPM in a patient with recent chemotherapy for colon cancer without electrolyte unbalance and otherwise unexplained causes. Moreover, the present case is an example of the unusual clinical ataxic variant, followed by complete recovery without any specific treatment. The diagnosis was confirmed by MRI, which showed a characteristic hyperintense signal abnormality in the central part of the pons with an unaffected outer rim. One month later, we observed complete resolution of clinical and radiological symptoms.
PMCID: PMC3098816  PMID: 21607027
Central pontine myelinolysis; Cerebellar ataxia; Chemotherapy; Complete recovery; Hyponatremia
14.  COMT inhibition with tolcapone in the treatment algorithm of patients with Parkinson’s disease (PD): relevance for motor and non-motor features 
Levodopa is the most effective treatment in Parkinson’s disease and the association with COMT inhibitors widens its plasma bioavailability and effectiveness. Tolcapone is a potent COMT inhibitor whose utilization in PD is limited due to safety concerns on liver toxicity. However, recent data indicate that if liver function is actively monitored, tolerability is no worse than other currently available therapies. By contrast, administration of tolcapone is associated with significant clinical improvement and benefit involves also non-motor features. In this review we discuss the rationale for the use of tolcapone in association with levodopa and other treatments in PD, and we provide an indirect comparison of current strategies to reduce “off” time. We propose that future guidelines include a trial with tolcapone in all PD patients who continue to complain about motor fluctuations despite treatment with entacapone and/or MAO-B inhibitors. Moreover, we suggest that tolcapone should be considered before surgical or infusional strategies are applied.
PMCID: PMC2515921  PMID: 18728767
Parkinson’s disease; levodopa; motor fluctuations; COMT inhibitors; tolcapone

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