Statin Use and Its Association with Essential Tremor and Parkinson s Disease

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1 Originl Pper Received: April 24, 2016 Accepted: My 6, 2016 Published online: June 16, 2016 Sttin Use nd Its Assocition with Essentil Tremor nd Prkinson s Disese Sherif Y. Shlby Eln D. Louis c Deprtment of Neurology, nd b Center for Neuroepidemiology nd Clinicl Neurologicl Reserch, Yle School of Medicine, nd c Deprtment of Chronic Disese Epidemiology, Yle School of Public Helth, Yle University, New Hven, Conn., USA Key Words Essentil tremor Prkinson s disese Tremor disorders Epidemiology Sttins Abstrct Bckground: Sttins hve potent nti-inflmmtory nd immunomodulting effects, nd my hve neuroprotective properties in ptients with Prkinson s disese (PD). There re no studies bout the use of sttins in the relted tremor disorder, essentil tremor (ET). We determined whether sttin use differed in ET cses vs. controls nd PD cses vs. controls. Methods: One hundred nd thirty nine ET cses, 108 PD cses, nd 124 controls prticipted in reserch study of the epidemiology of movement disorders. They were frequency mtched bsed on ge nd gender. Sttin use ws ssessed by self-report. Results: In djusted logistic regression nlyses, sttin use (current or ever) ws inversely ssocited with PD (ORs ), with mrginl vlues (p vlues = ). In similr djusted models, ET ws not ssocited with sttin use (p vlues = ). However, ET ws inversely ssocited with longer-term sttin use (djusted OR 0.27, p vlues = ). Conclusions: We observed mrginlly significnt inverse ssocition between PD nd sttin use. Although in primry nlyses we found no evidence tht sttin use ws protective in ET, there ws n inverse ssocition in nlyses tht ssessed longer term use of sttins. Further observtionl studies re wrrnted S. Krger AG, Bsel Introduction Sttins hve potent nti-inflmmtory nd immunomodulting effects, thereby leding to the hypothesis tht these gents hve neuroprotective properties [1, 2]. A sizble number of studies hve exmined the ssocition between sttin use nd odds or risk of Prkinson s disese (PD), nd these hve generted mixed results [3 6]. Thus, in study in Denmrk of 1,931 PD ptients nd 9,651 mtched controls, there ws n inverse ssocition between PD dignosis nd short-term ( 1 yer) sttin use. However, longer durtion sttin use ws not ssocited with PD [3]. There ws no ssocition between PD nd sttin use in cse control nlysis using the United Kingdom-Bsed Generl Prctice Reserch Dtbse [6]. However, long-term sttin use ( 5 yers) ws inversely ssocited with PD in smple of 312 PD ptients nd 342 controls from 3 rurl Cliforni counties [5]. Attempting E-Mil krger@krger.com S. Krger AG, Bsel /16/ $39.50/0 Eln D. Louis, MD, MS Deprtment of Neurology Yle School of Medicine, Yle University LCI 710, 15 York Street, PO Box , New Hven, CT (USA) E-Mil yle.edu

2 to summrize dt from eleven studies, recent metnlysis concluded tht sttin use ws ssocited with reduced risk of PD (summry reltive risk = 0.81, 95% CI ) [7]. Essentil tremor (ET) is tremor disorder tht shres number of clinicl nd etiologicl fetures with PD [8 11]. Furthermore, in some postmortem studies, ET cses hve prepondernce of Lewy bodies compred to gemtched controls [12]. Hence, number of studies hve exmined risk fctors for PD mong ET cses [13, 14]. Yet to our knowledge, there hve been no studies of the use of sttins in ET. Our gol ws to determine whether sttin use differed in ET cses vs. norml controls. We lso enrolled group with PD, compring them to controls s well. These nlyses cpitlized on the enrollment of ptients with ET nd PD s well s controls in reserch study of the epidemiology of movement disorders [15]. Methods Prticipnts nd Evlution ET cses, PD cses, nd controls were enrolled in study of the epidemiology of movement disorders t Columbi University Medicl Center (CUMC; ) [15]. All cses hd received dignosis of ET or PD from their treting neurologist, one of the movement disorder neurologists t the Neurologicl Institute, CUMC. To fcilitte enrollment, ET nd PD cses were confined to those living in geogrphicl re within 2 h driving distnce of CUMC [10]. One of the uthors (E.D.L.) reviewed the office records of ll selected ET nd PD cses, nd confirmed the dignoses of PD using published dignostic criteri [16]. ET cses lso underwent videotped tremor exmintion nd dignostic confirmtion s described further below. Controls were recruited during the sme time period s cses. These controls were identified using rndom digit telephone diling within defined set of telephone re codes represented by the cses within the New York Metropolitn re, nd were selected from the sme source popultion s the cses. During recruitment, controls were frequency-mtched to ET cses bsed on ge. The CUMC Internl Review Bord pproved ll study procedures. Written informed consent ws obtined upon enrollment. During the in-person evlution, conducted on ll ET cses, PD cses nd controls, the trined reserch worker dministered clinicl questionnires (medicl history nd medictions). This included min, 30-item, structured questionnire tht elicited dt on history of sttin use. This mediction questionnire ws similr to the one used in n erlier study [17] investigting nonsteroidl nti-inflmmtory medictions mong ET cses. The questionnire initilly sked, Do you currently tke medictions to lower your cholesterol? nd In the pst did you ever tke medictions for cholesterol? If they nswered no to both questions, the questionnire ws terminted. If they nswered yes to either question, we then further sked bout the prescription of the common types of sttin mediction, durtion of use, nd current nd highest dose ever prescribed in mg. Also, we ctegorized sttins into lipophilic (e.g. torvsttin, simvsttin, nd pitvsttin) nd hydrophilic (e.g. rosuvsttin, fluvsttin, nd prvsttin), s lipophilic sttins cross the blood brin brrier nd demonstrte neuroprotective role [18, 19]. Furthermore, we investigted whether sttin use for up to 12 yers ws ssocited with PD or ET; this ws bsed on published study demonstrting neuroprotective role of sttin use in this time frme [20]. Medicl comorbidity ws ssessed using the Cumultive Illness Rting Scle (CIRS), in which the severity of medicl problems (0 (none) 3 (severe)) ws rted in 14 body systems (e.g. crdic, respirtory) nd CIRS score ws ssigned (rnge 0 42 (mximl co-morbidity)) to ech prticipnt [21]. Yers since the time of lst hospitliztion, mesure of medicl comorbidity, ws lso ssessed. Tobcco exposure ws ssessed, nd cigrette smoking ws clculted in pck yers; prticipnts who never smoked were ssigned 0 for pck yers. We lso recorded whether the prticipnt hd dignosis of dibetes mellitus, which hs been ssocited with sttin use [22]. Furthermore, with the subject stnding, mesurements were tken of body weight to the nerest 0.1 pound using blnce scle designed for field surveys (Scle- Tronix 5600, White Plins, N.Y., USA). Height ws mesured to the nerest 0.5 cm using movble nthropometer (GPM Mrtin Type, Pfister Inc., Crlstdt, N.J., USA). Body mss index (BMI) ws clculted s weight in kg divided by the squre of height in meters. All ET cses nd controls lso underwent stndrdized videotped tremor exmintion, which included tests of posturl nd kinetic tremors nd ssessments for the presence of other involuntry movements. The im ws to use the videotpe to crefully vlidte ET dignoses (nd lck thereof in controls) using rigorous reserch-grde dignostic criteri [23]. Thus, ech videotpe ws reviewed by senior neurologist specilizing in movement disorders (E.D.L.) who confirmed the ET dignoses using Wshington Heights-Inwood Genetic Study of ET (WHIGET) dignostic criteri (moderte or greter mplitude kinetic tremor (tremor rting 2) during 3 or more tests or hed tremor, in the bsence of PD, or nother cuse) [23]. The WHIGET tremor rting scle ws lso used to rte posturl nd kinetic tremor during ech test: 0 (none), 1 (mild), 2 (moderte), 3 (severe). These rtings resulted in totl tremor score (rnge 0 36). Finl Smple Selection To frequency mtch by ge nd gender cross ll 3 dignostic groups, we excluded 82 (18.1%) of 453 enrollees. This mtching ws performed by selecting group of individuls in ech of the 2 remining dignostic groups (PD, controls) whose ge nd gender conformed to the distribution observed in the ET cses. This mtching ws performed within ech dignostic ctegory blinded to ll dt other thn ge nd gender. The finl smple included 371 enrollees: 139 (100%) of 139 ET cses, 108 (80.6%) of 134 PD cses, nd 124 (68.9%) of 180 controls. Sttisticl Anlyses Anlyses were performed using the sttisticl softwre pckge SPSS (version 21.0; SPSS, Inc., Chicgo, Ill., USA). We compred demogrphic nd clinicl chrcteristics cross the 3 dignostic groups (PD, ET, controls; tble 1 ). When vribles were not normlly distributed (i.e. Kolmogorov Smirnov test sttistic p vlue <0.05), non-prmetric tests were used. When difference ws 12 Shlby/Louis

3 Tble 1. Demogrphic dt nd comorbidities of 371 prticipnts PD ET Control p vlue Numbers Age, yers 71.3±6.4 (71.0) 71.9±12.8 (73.0) 71.5±9.1 (72.0) 0.12 Femle gender 60 (55.6) 73 (52.5) 67 (54.0) 0.89 b Eduction, yers 16.3±2.8 (16.0) 16.1±2.6 (16.0) 16.2±2.7 (16.0) 0.61 Cigrette pck yers 9.3±17.8 (0.0) 11.4±18.9 (1.0) 10.6±16.1 (2.0) 0.21 BMI, kg/m ±5.7 (24.3) 25.3±5.1 (25.0) 26.0±7.0 (25.6) 0.35 Number of prescription medictions 5.8±2.8 (5.0)* 4.9±3.2 (4.0)* 3.5±2.9 (3.0) <0.001 Yers since lst hospitliztion 11.5±16.0 (4.0) 11.5±16.4 (4.0) 12.4±14.6 (7.0) 0.44 CIRS score 7.2±3.2 (7.0) 7.3±3.6 (7.0) 6.8±3.9 (7.0) 0.48 Dibetes mellitus 9 (8.4) 11 (8.1) 14 (11.4) 0.62 b Dily levodop dosge, mg 529.8±394.7 NA NA NA Vlues re men ± SD (medin) or number (percentge). Kruskl Wllis test compring ll 3 groups. b Chi-squre test compring ll 3 groups. * Significntly different from controls (p < 0.05, Mnn Whitney U test). NA = Not pplicble. detected cross the 3 groups, we further compred ech dignostic group to controls (i.e. ET vs. controls, PD vs. controls). All tests were 2-sided, nd significnce ws ccepted t the 5% level. To ssess the reltionship of ET nd PD to sttin use we used logistic regression nlyses. We first ssessed whether sttin use (current or ever) ws ssocited with either ET or PD. Also, we ctegorized sttins into lipophilic (e.g. torvsttin, simvsttin, nd pitvsttin) nd hydrophilic (e.g. rosuvsttin, fluvsttin, nd prvsttin), s lipophilic sttins cross the blood brin brrier nd demonstrte neuroprotective role. We then ssessed whether longterm sttin use (i.e. for up to 12 yers) ws ssocited with ET or PD. We lso used n lterntive cut point for long-term sttin use (i.e. for up to 10 yers). In these logistic regression nlyses, we begn with n undjusted model. Then, in djusted models, we first considered vribles tht were ssocited with both the movement disorder nd with sttin use ( conservtive model (more restrictive criteri for confounding)) nd then considered vribles tht were ssocited with either the movement disorder or with sttin use ( liberl model (less restrictive criteri for confounding)) t p < 0.05 level. These nlyses generted ORs with 95% CIs. Given the lrge number of comprisons in the secondry nlysis of specific sttin medictions (n = 8; tble 2 ), significnt p vlue for the secondry nlysis ws conservtively set t <0.006 (i.e. 0.05/8); in this nlysis, p vlues between nd 0.05 were viewed s mrginlly significnt. In other nlyses, Mnn Whitney U test ws used to determine whether totl tremor score in ET differed between ctegories of sttin use (current or ever use yes vs. no). Furthermore, we used Spermn s correltion coefficient to ssess the reltionship between tremor severity (i.e. totl tremor score) in ET nd durtion of sttin use in yers. Study Power Using published dt on the use of sttins in PD cses vs. controls (17% of PD cses nd 34% of controls used cholesterol lowering drugs) [4], we determined tht smple size of 103 per group would provide us with 80% power (ssuming lph = 0.05). Thus, our smple of 139 ET, 108 PD nd 124 controls (men = 124 per group) ws dequtely powered to detect cse control differences similr to those reported previously. Results The 3 groups were similr with respect to ge, gender, eduction, cigrette pck yers, BMI, nd vriety of dditionl clinicl fetures ( tble 1 ). The totl number of prescription medictions ws significntly higher in PD nd ET cses thn controls ( tble 1 ). The groups were similr with respect to the use (ever) of sttins nd with respect to the use (current) of sttins ( tble 2 ). The durtion of sttin use ws no different in ET nd PD cses thn controls. However, significntly lower proportion of ET cses thn controls hd used sttins for up to 12 yers (chi-squre test = 5.60, p = 0.018) nd for up to 10 yers (chi-squre test = 7.34; p = 0.007; tble 2 ). When compring the 3 groups with respect to the proportion tht used ech type of sttin, there were no group differences ( tble 2 ). Using our control smple, we compred sttin users vs. non sttin users ( tble 3 ). Sttin users re older, more likely to be mle, hd more cigrette pck yers, took more prescription medictions, hd higher CIRS scores, nd were mrginlly more likely to hve dibetes mellitus (tble 3 ). Sttin Use nd Its Assocition with ET nd PD 13

4 Tble 2. Sttin use nd dosge mong 371 prticipnts PD ET Control p vlue Numbers Ever (pst or current) sttin use 54 (50.0) 74 (53.2) 59 (47.6) 0.65 b Ever (pst or current) hydrophilic sttin use 9 (8.3) 16 (11.5) 12 (9.7) 0.70 b Ever (pst or current) lipophilic sttin use 42 (38.9) 50 (36.0) 45 (36.3) 0.88 b Current sttin use 49 (45.4) 71 (51.1) 52 (41.9) 0.32 b Durtion (yers) of sttin use 5.8±5.4 (5.0) 6.5±7.1 (5.0) 4.8±4.6 (3.5) 0.71 Sttin use for up to 10 yers 100 (92.6) 120 (86.3)* 119 (96.0) 0.02 b Sttin use for up to 12 yers 101 (93.5) 124 (89.2)* 120 (96.8) 0.05 b Simvsttin use Yes 20 (18.5) 21 (15.1) 24 (19.4) 0.63 b Current dose 24.5±16.7 (20.0) 28.8±15.7 (20.0) 27.0±11.1 (20.0) 0.37 Highest dose 26.0±16.7 (20.0) 29.3±15.2 (20.0) 30.4±18.7 (20.0) 0.53 Atorvsttin use Yes 21 (19.4) 27 (19.4) 21 (16.9) 0.84 b Current dose 26.0±22.3 (15.0) 20.8±16.2 (20.0) 20.0±19.4 (10.0) 0.42 Highest dose 28.0±25.3 (15.0) 22.3±19.6 (20.0) 19.1±19.1 (10.0) 0.38 Rosuvsttin use Yes 4 (3.7) 9 (6.5) 8 (6.5) 0.74 b Current dose 20.3±19.5 (20.0) 12.2±4.4 (10.0) 16.3±11.6 (10.0) 0.78 Highest dose 27.0±22.5 (40.0) 13.3±5.0 (10.0) 17.9±11.5 (10.0) 0.57 Prvsttin use Yes 5 (4.6) 7 (5.0) 4 (3.2) 0.76 b Current dose 55.0±30.0 (40.0) 37.1±7.6 (40.0) 45.0±25.2 (40.0) 0.47 Highest dose 65.0±30.0 (60.0) 37.1±7.6 (40.0) 45.0±25.2 (40.0) 0.19 Lovsttin use Yes 3 (5.4) 2 (2.2) 1 (1.4) 0.37 b Current dose 25.0±7.1 (25.0) 46.7±30.6 (40.0) 10.0±0.0 (10.0) 0.25 Highest dose 25.0±7.1 (25.0) 46.7±30.6 (40.0) 10.0±0.0 (10.0) 0.25 Pitvsttin use Yes 1 (0.9) 2 (1.4) 1 (0.8) 0.87 b Current dose 1.0±0.0 (1.0) 2.0±0.0 (2.0) 2.0±0.0 (2.0) 0.37 Highest dose 1.0±0.0 (1.0) 2.0±0.0 (2.0) 2.0±0.0 (2.0) 0.37 Ezetimibe use Yes 0 (0.0) 6 (4.3) 1 (0.8) 0.03 b Current dose NA 10.0±0.0 (10.0) 10.0±0.0 (10.0) 0.99 Highest dose NA 10.0±0.0 (10.0) 10.0±0.0 (10.0) 0.99 Fluvsttin use Yes 0 (0.0) 0 (0.0) 0 (0.0) Current dose NA NA NA Highest dose NA NA NA NA Other sttin use Yes 0 (0.0) 3 (3.3) 2 (2.8) 0.40 b Current dose NA 505.0±646.3 (145.0) 145±0.0 (145.0) 0.99 Highest dose NA 505.0±646.3 (145.0) 145±0.0 (145.0) 0.99 Vlues re men ± SD (medin) or number (percentge). Kruskl Wllis test compring ll 3 groups. b Chi-squre test compring ll 3 groups. * Significntly different from controls (p < 0.05, chi-squre test). In n undjusted logistic regression nlysis, sttin use (current or ever) ws not ssocited with either PD or ET ( tble 4 ). In djusted logistic regression nlyses, sttin use (current or ever) ws inversely ssocited with PD (OR 0.56 (conservtive model) nd OR 0.63 (liberl model)), with mrginl vlues (p vlues = ; tble 4 ). In djusted models, ET ws not ssocited with sttin use (p vlues = ; tble 4 ). However, ET ws inversely ssocited with sttin use for up to 12 yers (OR 0.28 (undjusted model), OR 0.27 (conservtive 14 Shlby/Louis

5 Tble 3. Chrcteristics of sttin users vs. non users mong controls Sttin users Not sttin users p vlue Numbers Age, yers 73.7±8.3 (73.0) 69.5±9.5 (71.0) Femle gender 25 (42.3) 42 (64.6) 0.01 b Eduction, yers 16.4±2.5 (16.0) 16.0±2.9 (16.0) 0.40 Cigrette pck yers 11.9±13.9 (8.0) 9.4±17.7 (0.0) 0.02 BMI, kg/m ±5.0 (26.0) 25.9±8.3 (24.1) 0.32 Number of prescription medictions 4.8±2.9 (4.5) 2.3±2.4 (1.0) < Yers since lst hospitliztion 11.4±13.4 (7.0) 13.4±15.7 (7.0) 0.49 CIRS score 7.8±4.0 (7.0) 5.9±3.6 (6.0) Dibetes mellitus 10 (17.0) 4 (6.1) 0.06 b Vlues re men ± SD (medin) or number (percentge). Mnn Whitney U test compring 2 groups. b Chi-squre test compring 2 groups. Tble 4. Logistic regression nlysis of sttin use in PD nd ET Dignosis Undjusted model Liberl djusted model 1 Conservtive djusted model 2 OR 95% CI significnce OR 95% CI significnce OR 95% CI significnce Sttin use (current or ever) PD ET Sttin use (current or ever) (lipophilic) PD ET Sttin use (current or ever) (hydrophilic) PD ET Sttin use for up to 12 yers PD ET Sttin use for up to 10 yers PD ET Adjusted for number of prescription medictions, ge in yers, gender, pck yers (cigrettes), nd CIRS. 2 Adjusted for number of prescription medictions. model) nd OR 0.27 (liberl model), p vlues = ; tble 4 ). Using n lterntive cut point for longterm sttin use (i.e. for up to 10 yers), it ws found tht the ssocition with ET ws even more robust (OR 0.27 (undjusted model), OR 0.27 (conservtive model) nd OR 0.26 (liberl model), p vlues = ; tble 4 ). By contrst, PD ws not ssocited with such long-term sttin use. Tremor severity (i.e. totl tremor score) ws not ssocited with the ctegory of sttin use (yes vs. no (cur- Sttin Use nd Its Assocition with ET nd PD 15

6 rent or ever use; p = 0.83, Mnn Whitney U test)). Furthermore, totl tremor score in ET did not correlte with the durtion of sttin use (Spermn s r = 0.04; p = 0.64). Discussion We investigted whether ET or PD ws ssocited with sttin use. In n djusted model, PD ws inversely ssocited with sttin use (current or ever, OR 0.56), but with mrginl sttisticl significnce (p = 0.07). This inverse ssocition between PD nd sttin use hs been previously observed in lrger studies [5, 7]. ET ws not ssocited with sttin use (current or ever); however, there ws n inverse ssocition in n nlysis tht ssessed longerterm use of sttins. ET is chronic, progressive neurologicl disese; it my even be fmily of diseses. The biologicl mechnisms tht underlie ET re not entirely cler lthough there is considerble evidence to support neurodegenertive mechnisms [24 26]. Whether the specific mechnisms involve oxidtive stress or neuroinflmmtion is not known, lthough it ws with this possibility in mind tht we chose to exmine the ssocition between sttin use nd ET. Sttins my reduce oxidtive stress nd neuroinflmmtion. Their links with PD, long with the links between PD nd ET, provided rtionle to study their use in ET in these nlyses [11, 27]. In our primry nlyses, we did not find evidence of n ssocition between ET nd sttin use; however, in n nlysis tht ssessed longer-term use, there ws n inverse ssocition. In prior study of 156 ET cses nd 220 controls, we conducted detiled dietry ssessments nd tested the hypothesis tht diminished use of nutritionl ntioxidnts ws ssocited with ET. In tht study, there ws no evidence tht current nutritionl ntioxidnt exposure differed in ET cses nd controls [28]. Further studies re wrrnted. This study should be interpreted within the context of severl limittions. First, this ws cse control study rther thn cohort study. This precludes direct inferences bout cuslity in the reltionship between sttin use nd neurologicl diseses. Second, we ssessed the use of sttins by self-report rther thn phrmcy records, rising potentil questions bout the vlidity of the primry dt. The confirmtion of prior finding of n inverse ssocition between PD nd sttin use, however, suggests tht the self-report dt re to some extent vlid. Finlly, the study ws powered to detect doubling in the proportion of sttin users cross dignostic groups; more subtle group differences might not hve been detected. Strengths of the study include the novelty of the question we pose (i.e. the ssocition between sttin use nd other movement disorders side from PD), the enrollment of nerly 400 prticipnts, the fct tht cses hd ll received dignosis of ET or PD tht ws crefully ssigned by movement disorder neurologist (thereby lowering the risk of disese misclssifiction), the inclusion of disese group (PD) with well-known inverse ssocition with sttin use (i.e. enrollment of n internl control), the creful frequency mtching of our 3 dignostic groups by ge nd gender, the fct tht controls were crefully selected from the sme source popultion s the cses, nd the bility to ssess nd djust for the effects of numerous potentil confounding vribles. We observed mrginlly significnt inverse ssocition between PD nd sttin use. Although in primry nlyses we found no evidence tht sttin use ws protective in ET, there ws n inverse ssocition in n nlysis tht ssessed longer-term use of sttins. Further observtionl studies re wrrnted. Acknowledgments nd Funding All uthors hve no conflicts of interest. This study is supported by NIH (R01 NS nd R01 NS094607). References 1 Becker C, Meier CR: Sttins nd the risk of Prkinson disese: n updte on the controversy. Expert Opin Drug Sf 2009; 8: Wood WG, Eckert GP, Igbvbo U, Muller WE: Sttins nd neuroprotection: prescription to move the field forwrd. Ann N Y Acd Sci 2010; 1199: Ritz B, Mnthriprgd AD, Qin L, Schernhmmer E, Wermuth L, Olsen J, Friis S: Sttin use nd Prkinson s disese in Denmrk. Mov Disord 2010; 25: Hung X, Chen H, Miller WC, Milmn RB, Woodrd JL, Chen PC, Xing D, Murrow RW, Wng YZ, Poole C: Lower low-density lipoprotein cholesterol levels re ssocited with Prkinson s disese. Mov Disord 2007; 22: Whner AD, Bronstein JM, Bordelon YM, Ritz B: Sttin use nd the risk of Prkinson disese. Neurology 2008; 70(16 pt 2): Becker C, Jick SS, Meier CR: Use of sttins nd the risk of Prkinson s disese: retrospective cse-control study in the UK. Drug Sf 2008; 31: Bi S, Song Y, Hung X, Peng L, Ji J, Liu Y, Lu H: Sttin use nd the risk of Prkinson s disese: n updted met-nlysis. PLoS One 2016; 11:e Shlby/Louis

7 8 LRoi H, Louis ED: Assocition between essentil tremor nd other neurodegenertive diseses: wht is the epidemiologicl evidence? Neuroepidemiology 2011; 37: Vilrino-Guell C, Wider C, Ross OA, Jsinsk-Myg B, Kchergus J, Cobb SA, Soto-Ortolz AI, Behrouz B, Heckmn MG, Diehl NN, Test CM, Wszolek ZK, Uitti RJ, Jnkovic J, Louis ED, Clrk LN, Rjput A, Frrer MJ: Lingo1 nd lingo2 vrints re ssocited with essentil tremor nd Prkinson disese. Neurogenetics 2010; 11: Louis ED, Ottmn R: Is there one-wy street from essentil tremor to Prkinson s disese? Possible biologicl rmifictions. Eur J Neurol 2013; 20: Thengntt MA, Jnkovic J: The reltionship between essentil tremor nd Prkinson s disese. Prkinsonism Relt Disord 2016; 22(suppl 1):S162 S Louis ED, Fust PL, Vonsttel JP, Honig LS, Rjput A, Robinson CA, Rjput A, Phw R, Lyons KE, Ross GW, Borden S, Moskowitz CB, Lwton A, Hernndez N: Neuropthologicl chnges in essentil tremor: 33 cses compred with 21 controls. Brin 2007; 130(pt 12): Grci-Mrtin E, Mrtinez C, Alonso-Nvrro H, Benito-Leon J, Lorenzo-Betncor O, Pstor P, Lopez-Alburquerque T, Smrnch L, Lorenzo E, Agundez JA, Jimenez-Jimenez FJ: H1-mpt nd the risk for fmilil essentil tremor. PLoS One 2012; 7:e Louis ED, Benito-Leon J, Bermejo-Prej F; Neurologicl Disorders in Centrl Spin (NEDICES) Study Group: Popultion-bsed prospective study of cigrette smoking nd risk of incident essentil tremor. Neurology 2008; 70: Louis ED, Ro AK: Functionl spects of git in essentil tremor: comprison with gemtched Prkinson s disese cses, dystoni cses, nd controls. Tremor Other Hyperkinet Mov (N Y) 2015; 5:pii:tre Hughes AJ, Ben-Shlomo Y, Dniel SE, Lees AJ: Wht fetures improve the ccurcy of clinicl dignosis in Prkinson s disese: clinicopthologic study. Neurology 1992; 42: Pn J, Michlec M, Louis ED: Non-steroidl nti-inflmmtory drug use nd essentil tremor. Neuroepidemiology 2014; 43: Sierr S, Rmos MC, Molin P, Esteo C, Vzquez JA, Burgos JS: Sttins s neuroprotectnts: comprtive in vitro study of lipophilicity, blood-brin-brrier penetrtion, lowering of brin cholesterol, nd decrese of neuron cell deth. J Alzheimers Dis 2011; 23: Kim MC, Ahn Y, Jng SY, Cho KH, Hwng SH, Lee MG, Ko JS, Prk KH, Sim DS, Yoon NS, Yoon HJ, Kim KH, Hong YJ, Prk HW, Kim JH, Jeong MH, Cho JG, Prk JC, Kng JC: Comprison of clinicl outcomes of hydrophilic nd lipophilic sttins in ptients with cute myocrdil infrction. Koren J Intern Med 2011; 26: Go X, Simon KC, Schwrzschild MA, Ascherio A: Prospective study of sttin use nd risk of Prkinson disese. Arch Neurol 2012; 69: Linn BS, Linn MW, Gurel L: Cumultive illness rting scle. J Am Geritr Soc 1968; 16: Redberg RF, Ktz MH: Ressessing benefits nd risks of sttins. N Engl J Med 2012; 367: 776; uthor reply Louis ED, Ottmn R, Ford B, Pullmn S, Mrtinez M, Fhn S, Huser WA: The Wshington heights-inwood genetic study of essentil tremor: methodologic issues in essentiltremor reserch. Neuroepidemiology 1997; 16: Benito-Leon J: Essentil tremor: neurodegenertive disese? Tremor Other Hyperkinet Mov 2014; 4: Bonuccelli U: Essentil tremor is neurodegenertive disese. J Neurl Trnsm (Vienn) 2012; 119: ; discussion Louis ED: Re-thinking the biology of essentil tremor: from models to morphology. Prkinsonism Relt Disord 2014; 20(suppl 1):S88 S Benito-Leon J, Louis ED, Bermejo-Prej F; Neurologicl Disorders in Centrl Spin Study Group: Risk of incident Prkinson s disese nd prkinsonism in essentil tremor: popultion bsed study. J Neurol Neurosurg Psychitry 2009; 80: Louis ED, Jurewicz EC, Prides MK: Csecontrol study of nutritionl ntioxidnt intke in essentil tremor. Neuroepidemiology 2005; 24: Sttin Use nd Its Assocition with ET nd PD 17