@article {1391, title = {Cardiovascular physiology in premotor Parkinson{\textquoteright}s disease: a neuroepidemiologic study.}, journal = {Mov Disord}, volume = {27}, year = {2012}, month = {2012 Jul}, pages = {988-95}, abstract = {

Changes in cardiovascular physiology in Parkinson{\textquoteright}s disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (>=1\%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P <= .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95\% CI, 1.02-2.07; P = .04) or any carotid stenosis (OR, 2.40; 95\% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset.

}, keywords = {Aged, Antiparkinson Agents, Cardiovascular Physiological Phenomena, Carotid Stenosis, Cohort Studies, Data Interpretation, Statistical, Dizziness, Electrocardiography, Female, Heart Rate, Hospitalization, Humans, Longitudinal Studies, Male, Movement Disorders, Neurologic Examination, Parkinson Disease, Risk, Ultrasonography}, issn = {1531-8257}, doi = {10.1002/mds.24979}, author = {Jain, Samay and Ton, Thanh G and Perera, Subashan and Zheng, Yan and Stein, Phyllis K and Thacker, Evan and Strotmeyer, Elsa S and Newman, Anne B and Longstreth, Will T} } @article {6864, title = {Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.}, journal = {Neurology}, volume = {84}, year = {2015}, month = {2015 Mar 3}, pages = {918-26}, abstract = {

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95\% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95\% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95\% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

}, keywords = {Cerebral Small Vessel Diseases, Collagen Type IV, Genetic Association Studies, Genetic Variation, Humans, Polymorphism, Single Nucleotide}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000001309}, author = {Rannikmae, Kristiina and Davies, Gail and Thomson, Pippa A and Bevan, Steve and Devan, William J and Falcone, Guido J and Traylor, Matthew and Anderson, Christopher D and Battey, Thomas W K and Radmanesh, Farid and Deka, Ranjan and Woo, Jessica G and Martin, Lisa J and Jimenez-Conde, Jordi and Selim, Magdy and Brown, Devin L and Silliman, Scott L and Kidwell, Chelsea S and Montaner, Joan and Langefeld, Carl D and Slowik, Agnieszka and Hansen, Bjorn M and Lindgren, Arne G and Meschia, James F and Fornage, Myriam and Bis, Joshua C and Debette, Stephanie and Ikram, Mohammad A and Longstreth, Will T and Schmidt, Reinhold and Zhang, Cathy R and Yang, Qiong and Sharma, Pankaj and Kittner, Steven J and Mitchell, Braxton D and Holliday, Elizabeth G and Levi, Christopher R and Attia, John and Rothwell, Peter M and Poole, Deborah L and Boncoraglio, Giorgio B and Psaty, Bruce M and Malik, Rainer and Rost, Natalia and Worrall, Bradford B and Dichgans, Martin and Van Agtmael, Tom and Woo, Daniel and Markus, Hugh S and Seshadri, Sudha and Rosand, Jonathan and Sudlow, Cathie L M} } @article {7788, title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 May 29}, pages = {2098}, abstract = {

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 {\texttimes} 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3\% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04362-x}, author = {Davies, Gail and Lam, Max and Harris, Sarah E and Trampush, Joey W and Luciano, Michelle and Hill, W David and Hagenaars, Saskia P and Ritchie, Stuart J and Marioni, Riccardo E and Fawns-Ritchie, Chloe and Liewald, David C M and Okely, Judith A and Ahola-Olli, Ari V and Barnes, Catriona L K and Bertram, Lars and Bis, Joshua C and Burdick, Katherine E and Christoforou, Andrea and DeRosse, Pamela and Djurovic, Srdjan and Espeseth, Thomas and Giakoumaki, Stella and Giddaluru, Sudheer and Gustavson, Daniel E and Hayward, Caroline and Hofer, Edith and Ikram, M Arfan and Karlsson, Robert and Knowles, Emma and Lahti, Jari and Leber, Markus and Li, Shuo and Mather, Karen A and Melle, Ingrid and Morris, Derek and Oldmeadow, Christopher and Palviainen, Teemu and Payton, Antony and Pazoki, Raha and Petrovic, Katja and Reynolds, Chandra A and Sargurupremraj, Muralidharan and Scholz, Markus and Smith, Jennifer A and Smith, Albert V and Terzikhan, Natalie and Thalamuthu, Anbupalam and Trompet, Stella and van der Lee, Sven J and Ware, Erin B and Windham, B Gwen and Wright, Margaret J and Yang, Jingyun and Yu, Jin and Ames, David and Amin, Najaf and Amouyel, Philippe and Andreassen, Ole A and Armstrong, Nicola J and Assareh, Amelia A and Attia, John R and Attix, Deborah and Avramopoulos, Dimitrios and Bennett, David A and B{\"o}hmer, Anne C and Boyle, Patricia A and Brodaty, Henry and Campbell, Harry and Cannon, Tyrone D and Cirulli, Elizabeth T and Congdon, Eliza and Conley, Emily Drabant and Corley, Janie and Cox, Simon R and Dale, Anders M and Dehghan, Abbas and Dick, Danielle and Dickinson, Dwight and Eriksson, Johan G and Evangelou, Evangelos and Faul, Jessica D and Ford, Ian and Freimer, Nelson A and Gao, He and Giegling, Ina and Gillespie, Nathan A and Gordon, Scott D and Gottesman, Rebecca F and Griswold, Michael E and Gudnason, Vilmundur and Harris, Tamara B and Hartmann, Annette M and Hatzimanolis, Alex and Heiss, Gerardo and Holliday, Elizabeth G and Joshi, Peter K and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Karlsson, Ida and Kleineidam, Luca and Knopman, David S and Kochan, Nicole A and Konte, Bettina and Kwok, John B and Le Hellard, Stephanie and Lee, Teresa and Lehtim{\"a}ki, Terho and Li, Shu-Chen and Liu, Tian and Koini, Marisa and London, Edythe and Longstreth, Will T and Lopez, Oscar L and Loukola, Anu and Luck, Tobias and Lundervold, Astri J and Lundquist, Anders and Lyytik{\"a}inen, Leo-Pekka and Martin, Nicholas G and Montgomery, Grant W and Murray, Alison D and Need, Anna C and Noordam, Raymond and Nyberg, Lars and Ollier, William and Papenberg, Goran and Pattie, Alison and Polasek, Ozren and Poldrack, Russell A and Psaty, Bruce M and Reppermund, Simone and Riedel-Heller, Steffi G and Rose, Richard J and Rotter, Jerome I and Roussos, Panos and Rovio, Suvi P and Saba, Yasaman and Sabb, Fred W and Sachdev, Perminder S and Satizabal, Claudia L and Schmid, Matthias and Scott, Rodney J and Scult, Matthew A and Simino, Jeannette and Slagboom, P Eline and Smyrnis, Nikolaos and Soumar{\'e}, A{\"\i}cha and Stefanis, Nikos C and Stott, David J and Straub, Richard E and Sundet, Kjetil and Taylor, Adele M and Taylor, Kent D and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andre and Vitart, Veronique and Voineskos, Aristotle N and Kaprio, Jaakko and Wagner, Michael and Wagner, Holger and Weinhold, Leonie and Wen, K Hoyan and Widen, Elisabeth and Yang, Qiong and Zhao, Wei and Adams, Hieab H H and Arking, Dan E and Bilder, Robert M and Bitsios, Panos and Boerwinkle, Eric and Chiba-Falek, Ornit and Corvin, Aiden and De Jager, Philip L and Debette, Stephanie and Donohoe, Gary and Elliott, Paul and Fitzpatrick, Annette L and Gill, Michael and Glahn, David C and H{\"a}gg, Sara and Hansell, Narelle K and Hariri, Ahmad R and Ikram, M Kamran and Jukema, J Wouter and Vuoksimaa, Eero and Keller, Matthew C and Kremen, William S and Launer, Lenore and Lindenberger, Ulman and Palotie, Aarno and Pedersen, Nancy L and Pendleton, Neil and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Raitakari, Olli T and Ramirez, Alfredo and Reinvang, Ivar and Rudan, Igor and Schmidt, Reinhold and Schmidt, Helena and Schofield, Peter W and Schofield, Peter R and Starr, John M and Steen, Vidar M and Trollor, Julian N and Turner, Steven T and van Duijn, Cornelia M and Villringer, Arno and Weinberger, Daniel R and Weir, David R and Wilson, James F and Malhotra, Anil and McIntosh, Andrew M and Gale, Catharine R and Seshadri, Sudha and Mosley, Thomas H and Bressler, Jan and Lencz, Todd and Deary, Ian J} } @article {8708, title = {Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study.}, journal = {Alzheimers Dement}, year = {2021}, month = {2021 Mar 31}, abstract = {

INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes.

METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer{\textquoteright}s disease (AD) and vascular dementia (VaD), was classified using standardized research criteria.

RESULTS: Cataracts were associated with AD (hazard ratio [HR]~=~1.34; 95\% confidence interval [CI]~=~1.01-1.80) and VaD/mixed dementia (HR~=~1.41; 95\% CI~=~1.02-1.95). AMD was associated with AD only (HR~=~1.87; 95\% CI~=~1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR~=~2.63; 95\% CI~=~1.10-6.27).

DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.

}, issn = {1552-5279}, doi = {10.1002/alz.12313}, author = {Hwang, Phillip H and Longstreth, Will T and Thielke, Stephen M and Francis, Courtney E and Carone, Marco and Kuller, Lewis H and Fitzpatrick, Annette L} }