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Authors: Goñi, Joaquín | Cervantes, Sebastián | Arrondo, Gonzalo | Lamet, Isabel | Pastor, Pau | Pastor, María A.

Article Type: Research Article

Abstract: The aim of our study was to elucidate whether specific patterns of gray matter loss were associated with apolipoprotein E ε4 (APOE ε4) and microtubule-associated protein tau (MAPT)-H1) genetic variants in subjects with mild cognitive impairment (MCI) at a baseline visit. Gray matter voxel-based morphometry analysis of T1 magnetic resonance imaging scans were performed in 65 amnestic-MCI subjects. MCI APOE ε4 carriers compared with non-carriers showed increased brain atrophy in right hippocampus and rostral amygdala, superior and middle temporal gyrus, and right parietal operculum, including inferior frontal gyrus, inferior parietal, and supramarginal gyrus. MAPT-H1/H1 MCI carriers showed an increased bilateral …atrophy in superior frontal gyri (including frontal eye fields and left prefrontal cortex) and precentral gyrus but also unilateral left atrophy in the inferior temporal gyrus and calcarine gyrus. In addition, MCI subjects carrying both APOE ε4 and MAPT-H1/H1 variants showed gray matter loss in the supplementary motor area and right pre- and postcentral gyri. The effect of APOE ε4 on gray matter loss in right hippocampus suggests that, at least in some AD sub-types, the neuronal vulnerability could be increased in the right hemisphere. The pattern of frontal gray matter loss observed among MCI MAPT H1/H1 carriers has also been found in other tauopathies, suggesting that MCI may share etiological factors with other tauopathies. Frontal and parietal cortex vulnerability was found when adding MAPT H1/H1 and APOE ε4 effects, suggesting a synergistic effect of these variants. These results could be due to changes in APOE ε4 and MAPT expression. Show more

Keywords: APOE, genetic risk, genetics, magnetic resonance imaging, MAPT, mild cognitive impairment, single nucleotide polymorphism, tau, voxel based morphometry, Alzheimer disease

DOI: 10.3233/JAD-2012-121174

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1009-1019, 2013

Authors: Álvarez, Ignacio | Aguilar, Miquel | González, Jose Manuel | Ysamat, Montse | Lorenzo-Bosquet, Carles | Alonso, Alvaro | Tartari, Juan Pablo | Romero, Silvia | Diez-Fairen, Monica | Carcel, Maria | Pujalte, Francisco | Pastor, Pau

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer’s disease (AD); therefore, internal validation is recommended. Objective: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment. Methods: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA. Results: Amyloid-PET …was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1–42 (Aβ42 ) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2  = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2  = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups. Conclusions: CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-170753

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 135-143, 2018

Authors: Samaranch, Lluís | Cervantes, Sebastián | Barabash, Ana | Alonso, Alvaro | Cabranes, José Antonio | Lamet, Isabel | Ancín, Inés | Lorenzo, Elena | Martínez-Lage, Pablo | Marcos, Alberto | Clarimón, Jordi | Alcolea, Daniel | Lleó, Alberto | Blesa, Rafael | Gómez-Isla, Teresa | Pastor, Pau

Article Type: Research Article

Abstract: Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n = 319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that …MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio = 1.45; 95% CI = 1.04–2.02; p = 0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio = 1.47; 95% CI = 1.06–2.04; p = 0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio = 2.24, 95% CI = 1.40–3.58; p = 0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition. Show more

Keywords: Alzheimer's disease, APOE, interaction, genetics, microtubule-associated tau protein, MAPT, mild cognitive impairment

DOI: 10.3233/JAD-2010-101011

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1065-1071, 2010

Authors: Luis, Elkin | Ortiz, Alexandra | Eudave, Luis | Ortega-Cubero, Sara | Borroni, Barbara | van der Zee, Julie | Gazzina, Stefano | Caroppo, Paola | Rubino, Elisa | D’Agata, Federico | Le Ber, Isabelle | Santana, Isabel | Cunha, Gil | Almeida, Maria R. | Boutoleau-Bretonnière, Claire | Hannequin, Didier | Wallon, David | Rainero, Innocenzo | Galimberti, Daniela | Van Broeckhoven, Christine | Pastor, Maria A. | Pastor, Pau

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1 ), among other genes. Rare SQSTM1 gene mutations have been associated with Paget’s disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n  = 10), compared …with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD ; n  = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n  = 20). The groups were matched according to current age, disease duration, and gender. Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern. Show more

Keywords: Dementia, frontotemporal dementia, SQSTM1 protein, voxel-based morphometry

DOI: 10.3233/JAD-160006

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 303-313, 2016

Authors: Timsina, Jigyasha | Gomez-Fonseca, Duber | Wang, Lihua | Do, Anh | Western, Dan | Alvarez, Ignacio | Aguilar, Miquel | Pastor, Pau | Henson, Rachel L. | Herries, Elizabeth | Xiong, Chengjie | Schindler, Suzanne E. | Fagan, Anne M. | Bateman, Randall J. | Farlow, Martin | Morris, John C. | Perrin, Richard J. | Moulder, Krista | Hassenstab, Jason | Vöglein, Jonathan | Chhatwal, Jasmeer | Mori, Hiroshi | Sung, Yun Ju | Cruchaga, Carlos

Article Type: Research Article

Abstract: Background: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. Objective: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer’s disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. Methods: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different …studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson’s correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. Results: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r  > 0.9). sTREM2 had a fair correlation (r  > 0.6), whereas SNAP-25 showed weak correlation (r  = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. Conclusion: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers. Show more

Keywords: Alzheimer’s disease, assays, cerebrospinal fluid biomarkers, correlation, SOMAscan

DOI: 10.3233/JAD-220399

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 193-207, 2022

Authors: Pastor, Pau | Moreno, Fermín | Clarimón, Jordi | Ruiz, Agustín | Combarros, Onofre | Calero, Miguel | de Munain, Adolfo López | Bullido, Maria J. | de Pancorbo, Marian M. | Carro, Eva | Antonell, Anna | Coto, Eliecer | Ortega-Cubero, Sara | Hernandez, Isabel | Tárraga, Lluís | Boada, Mercè | Lleó, Alberto | Dols-Icardo, Oriol | Kulisevsky, Jaime | Vázquez-Higuera, José Luis | Infante, Jon | Rábano, Alberto | Fernández-Blázquez, Miguel Ángel | Valentí, Meritxell | Indakoetxea, Begoña | Barandiarán, Myriam | Gorostidi, Ana | Frank-García, Ana | Sastre, Isabel | Lorenzo, Elena | Pastor, María A. | Elcoroaristizabal, Xabier | Lennarz, Martina | Maier, Wolfang | Rámirez, Alfredo | Serrano-Ríos, Manuel | Lee, Suzee E. | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer’s disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson’s disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p  = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p … = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ 4 noncarriers (OR = 1.14; p  = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p  = 0.0003) and PSP (OR = 3.18; p  = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ 4 AD. Show more

Keywords: A152T, Alzheimer’s disease, frontotemporal dementia, genetic association, H1H2, MAPT

DOI: 10.3233/JAD-150555

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 343-352, 2016

Authors: Santos García, Diego | García Roca, Lucía | de Deus Fonticoba, Teresa | Cores Bartolomé, Carlos | Naya Ríos, Lucía | Canfield, Héctor | Paz González, Jose M. | Martínez Miró, Cristina | Jesús, Silvia | Aguilar, Miquel | Pastor, Pau | Planellas, Lluís | Cosgaya, Marina | García Caldentey, Juan | Caballol, Nuria | Legarda, Ines | Hernández Vara, Jorge | Cabo, Iria | López Manzanares, Lydia | González Aramburu, Isabel | Ávila Rivera, Maria A. | Gómez Mayordomo, Víctor | Nogueira, Víctor | Puente, Víctor | Dotor García-Soto, Julio | Borrué, Carmen | Solano Vila, Berta | Álvarez Sauco, María | Vela, Lydia | Escalante, Sonia | Cubo, Esther | Carrillo Padilla, Francisco | Martínez Castrillo, Juan C. | Sánchez Alonso, Pilar | Alonso Losada, Maria G. | López Ariztegui, Nuria | Gastón, Itziar | Kulisevsky, Jaime | Blázquez Estrada, Marta | Seijo, Manuel | Rúiz Martínez, Javier | Valero, Caridad | Kurtis, Mónica | de Fábregues, Oriol | González Ardura, Jessica | Alonso Redondo, Ruben | Ordás, Carlos | López Díaz L, Luis M. | McAfee, Darrian | Martinez-Martin, Pablo | Mir, Pablo | COPPADIS Study Group

Article Type: Research Article

Abstract: Background: Constipation has been linked to cognitive impairment development in Parkinson’s disease (PD). Objective: Our aim was to analyze cognitive changes observed in PD patients and controls from a Spanish cohort with regards to the presence or not of constipation. Methods: PD patients and controls recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017 were followed-up during 2 years. The change in cognitive status from baseline (V0) to 2-year follow-up was assessed with the PD-CRS (Parkinson’s Disease Cognitive Rating Scale). Subjects with a score ≥1 on item 21 of the NMSS (Non-Motor Symptoms …Scale) at baseline (V0) were considered as “with constipation”. Regression analyses were applied for determining the contribution of constipation in cognitive changes. Results: At V0, 39.7% (198/499) of PD patients presented constipation compared to 11.4% of controls (14/123) (p  < 0.0001). No change was observed in cognitive status (PD-CRS total score) neither in controls without constipation (from 100.24±13.72 to 100.27±13.68; p  = 0.971) and with constipation (from 94.71±10.96 to 93.93±13.03; p  = 0.615). The PD-CRS total score decreased significantly in PD patients with constipation (from 89.14±15.36 to 85.97±18.09; p  < 0.0001; Coehn’s effect = –0.35) compared to patients without constipation (from 93.92±15.58 to 93.14±17.52; p  = 0.250) (p  = 0.018). In PD patients, to suffer from constipation at V0 was associated with a decrease in the PD-CRS total score from V0 to V2 (β= –0.1; 95% CI, –4.36 – –0.27; p  = 0.026) and having cognitive impairment at V2 (OR = 1.79; 95% CI, 1.01 – 3.17; p  = 0.045). Conclusion: Constipation is associated with cognitive decline in PD patients but not in controls. Show more

Keywords: Cognition, constipation, impairment, non-motor symptoms, Parkinson’s disease

DOI: 10.3233/JPD-212868

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 315-331, 2022

Authors: Santos García, Diego | de Deus Fonticoba, Teresa | Cores, Carlos | Suárez Castro, Ester | Hernández Vara, Jorge | Jesús, Silvia | Mir, Pablo | Cosgaya, Marina | José Martí, Maria | Pastor, Pau | Cabo, Iria | Seijo, Manuel | Legarda, Inés | Vives, Bárbara | Caballol, Nuria | Rúiz Martínez, Javier | Croitoru, Ioana | Cubo, Esther | Miranda, Javier | Alonso Losada, Maria Gema | Labandeira, Carmen | López Ariztegui, Nuria | Morales-Casado, Mabel | González Aramburu, Isabel | Infante, Jon | Escalante, Sonia | Bernardo, Noemí | Blázquez Estrada, Marta | Menéndez González, Manuel | García Caldentey, Juan | Borrué, Carmen | Vela, Lydia | Catalán, Maria José | Gómez Mayordomo, Víctor | Kurtis, Mónica | Prieto, Cristina | Ordás, Carlos | Nogueira, Víctor | López Manzanares, Lydia | Ávila Rivera, Maria Asunción | Puente, Victor | García Moreno, Jose Manuel | Solano Vila, Berta | Álvarez Sauco, María | Carrillo Padilla, Francisco | Martínez Castrillo, Juan Carlos | Sánchez Alonso, Pilar | Gastón, Itziar | Kulisevsky, Jaime | Valero, Caridad | de Fábregues, Oriol | González Ardura, Jessica | López Díaz, Luis Manuel | Martinez-Martin, Pablo

Article Type: Research Article

Abstract: Background: There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission. Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital …encounter 1-year after the baseline visit. Results: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH. Conclusion: Falls is an independent predictor of AH in PD patients. Show more

DOI: 10.3233/JPD-212539

Citation: Journal of Parkinson's Disease, vol. 13, no. 1, pp. 105-124, 2023

Authors: Santos García, Diego | Canfield, Hector | de Deus Fonticoba, Teresa | Cores Bartolomé, Carlos | Naya Ríos, Lucía | García Roca, Lucía | Martínez Miró, Cristina | Jesús, Silvia | Aguilar, Miquel | Pastor, Pau | Cosgaya, Marina | García Caldentey, Juan | Caballol, Nuria | Legarda, Inés | Hernández Vara, Jorge | Cabo, Iria | López Manzanares, Lydia | González Aramburu, Isabel | Ávila Rivera, María A. | Gómez Mayordomo, Víctor | Nogueira, Víctor | Puente, Víctor | Dotor, Julio | Borrué, Carmen | Solano Vila, Berta | Álvarez Sauco, María | Vela, Lydia | Escalante, Sonia | Cubo, Esther | Carrillo Padilla, Francisco | Martínez Castrillo, Juan C. | Sánchez Alonso, Pilar | Alonso Losada, Maria G. | López Ariztegui, Nuria | Gastón, Itziar | Kulisevsky, Jaime | Blázquez Estrada, Marta | Seijo, Manuel | Rúiz Martínez, Javier | Valero, Caridad | Kurtis, Mónica | de Fábregues, Oriol | González Ardura, Jessica | Alonso Redondo, Ruben | Ordás, Carlos | López Díaz, Luis M. | McAfee, Darrian | Martinez-Martin, Pablo | Mir, Pablo | COPPADIS Study Group

Article Type: Research Article

Abstract: Background: Motor phenotype (MP) can be associated with a different prognosis in Parkinson’s disease (PD), but it is not fixed and can change over time. Objective: Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort. Methods: PD patients who were recruited from January-2016 to November-2017 (baseline visit; V0) and evaluated again at a 2-year±30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this study.MP was calculated at both visits based on Jankovic classification in …TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers. Results: Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR  =  0.937) at V0 and a greater increase in the globalNMS burden (OR  =  1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up. Conclusion: The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly. Show more

Keywords: Changes, motor, Parkinson’s disease, phenotype, postural instability, gait difficulty, tremor

DOI: 10.3233/JPD-213004

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 935-955, 2022

Authors: Domenighetti, Cloé | Sugier, Pierre-Emmanuel | Sreelatha, Ashwin Ashok Kumar | Schulte, Claudia | Grover, Sandeep | Mohamed, Océane | Portugal, Berta | May, Patrick | Bobbili, Dheeraj R. | Radivojkov-Blagojevic, Milena | Lichtner, Peter | Singleton, Andrew B. | Hernandez, Dena G. | Edsall, Connor | Mellick, George D. | Zimprich, Alexander | Pirker, Walter | Rogaeva, Ekaterina | Lang, Anthony E. | Koks, Sulev | Taba, Pille | Lesage, Suzanne | Brice, Alexis | Corvol, Jean-Christophe | Chartier-Harlin, Marie-Christine | Mutez, Eugénie | Brockmann, Kathrin | Deutschländer, Angela B. | Hadjigeorgiou, Georges M. | Dardiotis, Efthimos | Stefanis, Leonidas | Simitsi, Athina Maria | Valente, Enza Maria | Petrucci, Simona | Duga, Stefano | Straniero, Letizia | Zecchinelli, Anna | Pezzoli, Gianni | Brighina, Laura | Ferrarese, Carlo | Annesi, Grazia | Quattrone, Andrea | Gagliardi, Monica | Matsuo, Hirotaka | Kawamura, Yusuke | Hattori, Nobutaka | Nishioka, Kenya | Chung, Sun Ju | Kim, Yun Joong | Kolber, Pierre | van de Warrenburg, Bart PC | Bloem, Bastiaan R. | Aasly, Jan | Toft, Mathias | Pihlstrøm, Lasse | Guedes, Leonor Correia | Ferreira, Joaquim J. | Bardien, Soraya | Carr, Jonathan | Tolosa, Eduardo | Ezquerra, Mario | Pastor, Pau | Diez-Fairen, Monica | Wirdefeldt, Karin | Pedersen, Nancy L. | Ran, Caroline | Belin, Andrea C. | Puschmann, Andreas | Hellberg, Clara | Clarke, Carl E. | Morrison, Karen E. | Tan, Manuela | Krainc, Dimitri | Burbulla, Lena F. | Farrer, Matt J. | Krüger, Rejko | Gasser, Thomas | Sharma, Manu | Elbaz, Alexis | on behalf of the Comprehensive Unbiaised Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (Courage-PD) consortium

Article Type: Research Article

Abstract: Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method …to compute odds ratios (ORIVW ) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p  = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p  = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. Show more

Keywords: Smoking, alcohol, coffee, Parkinson’s disease, Mendelian randomisation

DOI: 10.3233/JPD-212851

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 267-282, 2022