Observational Study

. 2024 Sep 10;103(5):e209699.

doi: 10.1212/WNL.0000000000209699. Epub 2024 Aug 7.

Long-Term Dementia Risk in Parkinson Disease

Julia Gallagher¹, Caroline Gochanour¹, Chelsea Caspell-Garcia¹, Roseanne D Dobkin¹, Dag Aarsland¹, Roy N Alcalay¹, Matthew J Barrett¹, Lana Chahine¹, Alice S Chen-Plotkin¹, Christopher S Coffey¹, Nabila Dahodwala¹, Jamie L Eberling¹, Alberto J Espay¹, James B Leverenz¹, Irene Litvan¹, Eugenia Mamikonyan¹, James Morley¹, Irene H Richard¹, Liana Rosenthal¹, Andrew D Siderowf¹, Tatyana Simuni¹, Michele K York¹, Allison W Willis¹, Sharon X Xie¹, Daniel Weintraub¹; Parkinson's Progression Markers Initiative¹

Collaborators, Affiliations

Collaborators

Parkinson's Progression Markers Initiative:
Kenneth Marek, Caroline Tanner, Tanya Simuni, Andrew Siderowf, Douglas Galasko, Lana Chahine, Christopher Coffey, Kalpana Merchant, Kathleen Poston, Roseanne Dobkin, Tatiana Foroud, Brit Mollenhauer, Dan Weintraub, Ethan Brown, Karl Kieburtz, Duygu Tosun-Turgut, Werner Poewe, Susan Bressman, Jan Hamer, Raymond James, Ekemini Riley, John Seibyl, Leslie Shaw, David Standaert, Sneha Mantri, Nabila Dahodwala, Michael Schwarzschild, Connie Marras, Hubert Fernandez, Ira Shoulson, Helen Rowbotham, Lucy Norcliffe-Kaufmann, Paola Casalin, Claudia Trenkwalder, Todd Sherer, Sohini Chowdhury, Mark Frasier, Jamie Eberling, Katie Kopil, Alyssa O'Grady, James Gibaldi, Maggie McGuire Kuhl, Leslie Kirsch, Emily Flagg, Bridget McMahon, Craig Stanley, Kim Fabrizio, Dixie Ecklund, Trevis Huff, Richard Peters, Janel Fedler, Laura Heathers, Christopher Hobbick, Gena Antonopoulos, Chelsea Caspell-Garcia, Michael Brumm, Arthur Toga, Karen Crawford, Andrew Singleton, Thomas Montine, Monica Korell, Ruth Schneider, Kelvin Chou, David Russell, Stewart Factor, Penelope Hogarth, Robert Hauser, Marie H Saint-Hilaire, David Shprecher, Kathrin Brockmann, Yen Tai, Paolo Barone, Stuart Isaacson, Alberto Espay, Maria Jose Martí, Eduardo Tolosa, Shu-Ching Hu, Emile Moukheiber, Jean-Christophe Corvol, Nir Giladi, Javier Ruiz-Martinez, Jan O Aasly, Leonidas Stefanis, Karen Marder, Arjun Tarakad, Tiago Mestre, Aleksandar Videnovic, Rajesh Pahwa, Mark Lew, Holly Shill, Amy Amara, Charles Adler, Maureen Leehey, Giulietta Riboldi, Nikolaus McFarland, Ron Postuma, Zoltan Mari, Nicola Pavese, Michele Hu, Norbert Brüggemann, Christine Klein, Bastiaan Bloem, Anisha Singh, Angela Stovall, Julie Festa, Lianne Ramia, Katrina Wakeman, Karen Williams, Courtney Blair, Krista Specketer, Diana Willeke, Jennifer Mule, Ella Hilt, Shawnees Peacock, Kori Ribb, Susan Ainscough, Lisbeth Pennente, Julia Brown, Christina Gruenwald, Barbara Sommerfeld, Farah Kausar, Alicia Garrido, Deborah Raymond, Ioana Croitoru, Anne Grete Kristiansen, Helen Mejia-Santana, Anjana Singh, Danica Nogo, Shawna Reddie, Samantha Murphy, Lauren O'Brien, Ashwini Ramachandran, Fnu Madhuri, Daniel Freire, Farah Ismail, Tom Osgood, Heidi Friedeck, Jenny Frisendahl, Ying Liu, Caitlin Romano, Kelly Clark, Kyle Rizer, Stephanie Carvalho, Sherri Mosovsky, Farah Sulaiman, Dora Valent, Raquel Lopes, Michelle Torreliza, Shira Paz, Victoria Kate Foster, Madita Grümmer, Myrthe Burgler, Sabine van Zundert, Christos Koros, Jamil Razzaque

Affiliation

¹ From the Departments of Neurology (J.G., A.S.C.-P., N.D., J.M., A.D.S., A.W.W., D.W.) and Psychiatry (E.M., D.W.), and Biostatistics and Epidemiology (S.X.X.), University of Pennsylvania, Philadelphia; Department of Biostatistics (C.G., C.C.-G., C.S.C.), University of Iowa; Department of Psychiatry (R.D.D.), Rutgers University, Newark, NJ; Department of Old Age Psychiatry (D.A.), Kings College London, UK; Neurological Institute (R.N.A.), Tel Aviv Sourasky Medical Center, Israel; Department of Neurology (R.N.A.), Columbia University Irving Medical Center, New York, NY; Department of Neurology (M.J.B.), Virginia Commonwealth University, Richmond, VA; Department of Neurology (L.C.), University of Pittsburgh, PA; The Michael J. Fox Foundation for Parkinson's Research (J.L.E.), New York, NY; James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Department of Neurology, University of Cincinnati; Cleveland Clinic (J.B.L.), Neurological Institute, Lou Ruvo Center for Brain Health, OH; Department of Neuroscience (I.L.), University of California San Diego; Parkinson's Disease Research, Education and Clinical Center (PADRECC) (J.M., D.W.), Crescenz Veteran's Affairs Medical Center, Philadelphia, PA; Department of Neurology (I.H.R.), University of Rochester, NY; Department of Neurology (L.R.), Johns Hopkins University, Baltimore, MD; and Department of Neurology (T.S.), Northwestern University, Chicago, IL; Departments of Neurology and Psychiatry and Behavioral Sciences (M.K.Y.), Baylor College of Medicine, Houston, TX.

PMID: 39110916
PMCID: PMC11318527
DOI: 10.1212/WNL.0000000000209699

Observational Study

Long-Term Dementia Risk in Parkinson Disease

Julia Gallagher et al. Neurology. 2024.

. 2024 Sep 10;103(5):e209699.

doi: 10.1212/WNL.0000000000209699. Epub 2024 Aug 7.

Authors

Collaborators

Parkinson's Progression Markers Initiative:
Kenneth Marek, Caroline Tanner, Tanya Simuni, Andrew Siderowf, Douglas Galasko, Lana Chahine, Christopher Coffey, Kalpana Merchant, Kathleen Poston, Roseanne Dobkin, Tatiana Foroud, Brit Mollenhauer, Dan Weintraub, Ethan Brown, Karl Kieburtz, Duygu Tosun-Turgut, Werner Poewe, Susan Bressman, Jan Hamer, Raymond James, Ekemini Riley, John Seibyl, Leslie Shaw, David Standaert, Sneha Mantri, Nabila Dahodwala, Michael Schwarzschild, Connie Marras, Hubert Fernandez, Ira Shoulson, Helen Rowbotham, Lucy Norcliffe-Kaufmann, Paola Casalin, Claudia Trenkwalder, Todd Sherer, Sohini Chowdhury, Mark Frasier, Jamie Eberling, Katie Kopil, Alyssa O'Grady, James Gibaldi, Maggie McGuire Kuhl, Leslie Kirsch, Emily Flagg, Bridget McMahon, Craig Stanley, Kim Fabrizio, Dixie Ecklund, Trevis Huff, Richard Peters, Janel Fedler, Laura Heathers, Christopher Hobbick, Gena Antonopoulos, Chelsea Caspell-Garcia, Michael Brumm, Arthur Toga, Karen Crawford, Andrew Singleton, Thomas Montine, Monica Korell, Ruth Schneider, Kelvin Chou, David Russell, Stewart Factor, Penelope Hogarth, Robert Hauser, Marie H Saint-Hilaire, David Shprecher, Kathrin Brockmann, Yen Tai, Paolo Barone, Stuart Isaacson, Alberto Espay, Maria Jose Martí, Eduardo Tolosa, Shu-Ching Hu, Emile Moukheiber, Jean-Christophe Corvol, Nir Giladi, Javier Ruiz-Martinez, Jan O Aasly, Leonidas Stefanis, Karen Marder, Arjun Tarakad, Tiago Mestre, Aleksandar Videnovic, Rajesh Pahwa, Mark Lew, Holly Shill, Amy Amara, Charles Adler, Maureen Leehey, Giulietta Riboldi, Nikolaus McFarland, Ron Postuma, Zoltan Mari, Nicola Pavese, Michele Hu, Norbert Brüggemann, Christine Klein, Bastiaan Bloem, Anisha Singh, Angela Stovall, Julie Festa, Lianne Ramia, Katrina Wakeman, Karen Williams, Courtney Blair, Krista Specketer, Diana Willeke, Jennifer Mule, Ella Hilt, Shawnees Peacock, Kori Ribb, Susan Ainscough, Lisbeth Pennente, Julia Brown, Christina Gruenwald, Barbara Sommerfeld, Farah Kausar, Alicia Garrido, Deborah Raymond, Ioana Croitoru, Anne Grete Kristiansen, Helen Mejia-Santana, Anjana Singh, Danica Nogo, Shawna Reddie, Samantha Murphy, Lauren O'Brien, Ashwini Ramachandran, Fnu Madhuri, Daniel Freire, Farah Ismail, Tom Osgood, Heidi Friedeck, Jenny Frisendahl, Ying Liu, Caitlin Romano, Kelly Clark, Kyle Rizer, Stephanie Carvalho, Sherri Mosovsky, Farah Sulaiman, Dora Valent, Raquel Lopes, Michelle Torreliza, Shira Paz, Victoria Kate Foster, Madita Grümmer, Myrthe Burgler, Sabine van Zundert, Christos Koros, Jamil Razzaque

Affiliation

¹ From the Departments of Neurology (J.G., A.S.C.-P., N.D., J.M., A.D.S., A.W.W., D.W.) and Psychiatry (E.M., D.W.), and Biostatistics and Epidemiology (S.X.X.), University of Pennsylvania, Philadelphia; Department of Biostatistics (C.G., C.C.-G., C.S.C.), University of Iowa; Department of Psychiatry (R.D.D.), Rutgers University, Newark, NJ; Department of Old Age Psychiatry (D.A.), Kings College London, UK; Neurological Institute (R.N.A.), Tel Aviv Sourasky Medical Center, Israel; Department of Neurology (R.N.A.), Columbia University Irving Medical Center, New York, NY; Department of Neurology (M.J.B.), Virginia Commonwealth University, Richmond, VA; Department of Neurology (L.C.), University of Pittsburgh, PA; The Michael J. Fox Foundation for Parkinson's Research (J.L.E.), New York, NY; James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Department of Neurology, University of Cincinnati; Cleveland Clinic (J.B.L.), Neurological Institute, Lou Ruvo Center for Brain Health, OH; Department of Neuroscience (I.L.), University of California San Diego; Parkinson's Disease Research, Education and Clinical Center (PADRECC) (J.M., D.W.), Crescenz Veteran's Affairs Medical Center, Philadelphia, PA; Department of Neurology (I.H.R.), University of Rochester, NY; Department of Neurology (L.R.), Johns Hopkins University, Baltimore, MD; and Department of Neurology (T.S.), Northwestern University, Chicago, IL; Departments of Neurology and Psychiatry and Behavioral Sciences (M.K.Y.), Baylor College of Medicine, Houston, TX.

PMID: 39110916
PMCID: PMC11318527
DOI: 10.1212/WNL.0000000000209699

Abstract

Background and objectives: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies.

Methods: Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point.

Results: For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years.

Discussion: Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.

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Conflict of interest statement

C. Gochanour, C. Caspell-Garcia, R.D. Dobkin, L.M. Chahine, C.S. Coffey, A.D. Siderowf, T. Simuni, M.K. York, and D. Weintraub receive financial support for their administrative roles on the PPMI study. R.D. Dobkin receives grant support from the Michael J. Fox Foundation and the VA Office of Rural Health. D. Aarsland has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, GE Health, and Sanofi, and has received consulting fees from H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, Biogen, and Takeda. R.N. Alcalay has received consultation fees from Capsida, Takeda, Sanofi, Biohaven and Gain Therapeutics (paid to institution), and has received research support from the Parkinson's Foundation, the Michael J. Fox Foundation, and the Silverstein Foundation. M.J. Barrett receives research funding from the NIH (R21AG077469, R21AG074368) and Kyowa Kirin Inc., and serves as site PI for clinical trials and studies sponsored by Biogen, the CHDI Foundation, Cognition Therapeutics, EIP Pharma, uniQure, the Parkinson's Foundation, and Prilenia Therapeutics. L.M. Chahine receives research support from the Michael J. Fox Foundation, the UPMC Competitive Medical Research Fund, NIH, and the University of Pittsburgh, is site investigator for a study sponsored by Biogen, has received consulting fees from the Michael J. Fox Foundation, and receives royalties from Elsevier and Wolters Kluwer (for authorship). A. Chen-Plotkin receives research support from the NIH and the Parker Family Chair, is the inventor of a patent held by the University of Pennsylvania pertaining to genetic approaches to treating frontotemporal dementia (receives royalties for licensing). C.S. Coffey receives grant funding from the Michael J. Fox Foundation and the National Institute for Neurological Disorders and Stroke. N. Dahodwala receives grant support from the NIH (R01NS125294, U19AG062418), the Michael J. Fox Foundation, the Parkinson's Foundation, and Genentech (clinical trial), has received honoraria from Mediflix, has received consulting fees from Genentech, and has received compensation for review of medical records for Post & Schell (law firm). A.J. Espay has received grant support from the NIH and the Michael J. Fox Foundation, has received personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Supernus (formerly, USWorldMeds), and Herantis Pharma, has received speaker honoraria from Avion, Amneal, and Supernus, has received publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer, is a cofounder of REGAIN Therapeutics, and is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” J.B. Leverenz has received research support from the NIH (P30AG072959, U01NS100610, U01AG073323), GE Healthcare, the Alzheimer's Association, and the Lewy Body Dementia Association. I. Litvan has received research support from the NIH (grants: 2R01AG038791-06A, U01NS100610, R25NS098999, U19 AG063911-1, and 1R21NS114764-01A1), the Michael J. Fox Foundation, the Parkinson's Foundation, the Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene, EIP-Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL UCB, is a member of the scientific advisory board for Amydis (no compensation received) and the Rossy PSP Program at the University of Toronto, and receives salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. J.F. Morley has received research funding from the NIH, the Michael J. Fox Foundation, the Department of Defense, and the Department of Veteran Affairs. I. Richard has received research and/or training grants from NIH, the Parkinson's Foundation, and the Michael J. Fox Foundation, and has served as a site investigator and/or coinvestigator for clinical research studies sponsored by industry grants to the University of Rochester, currently including F. Hoffman-La Roche Ltd., Acadia Pharm, and Jazz Pharmaceuticals. L. Rosenthal receives research support from the National Institute of Neurological Disorders and Stroke, the Daniel B. and Florence E. Green Family Foundation, and the Macks Family Foundation, and receives additional programmatic support from the Gordon and Marilyn Macklin Foundation, receives salary support from Biohaven Pharmaceuticals and Pfizer and for serving on the Clinical Events Committee for a research study with Functional Neuromodulation, and serves on the steering committees for the Parkinson Study Group's research study with both UCB and Bial Pharmaceuticals, has received personal honoraria for serving on an advisory board for Reata pharmaceuticals and Biohaven Pharmaceuticals. A.D. Siderowf has received consulting fees from Wave Life Sciences, Inhibikase, Prevail, Merck, Bial Biotech, and Takeda, has served on DSMBs for the Huntington Study Group and the Healey ALS Consortium (Massachusetts General Hospital), and has received grant funding from the Michael J. Fox Foundation, NIA, and the National Institute of Neurological Disorders and Stroke. T. Simuni has served as a consultant for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, the Michael J. Fox Foundation, Neuroderm, Sanofi, Sinopia, Roche, Takeda, and Vanqua Bio, has served on scientific advisory boards for AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23, Roche, Koneksa, Neuroderm, Sanofi, and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, and UCB, and has served as an investigator for National Institute of Neurological Disorders and Stroke, the Michael J. Fox Foundation, and the Parkinson's Foundation. M. York has received grant support from the NIH and the Michael J. Fox Foundation, and personal compensation as a consultant/scientific advisory board member for Bluerock, the Parkinson's Foundation, and RAD-PD. A. Willis receives financial support from NIH (grant R01NS099129), the Parkinson's Foundation, Acadia Pharmaceuticals Inc., and the University of Pennsylvania. D. Weintraub has received funding from the Michael J. Fox Foundation, the Alzheimer's Therapeutic Research Initiative (ATRI), the Alzheimer's Disease Cooperative Study (ACds0), the International Parkinson and Movement Disorder Society (IPMDS), NIH, the Parkinson's Foundation, the US Department of Veterans Affairs, and Acadia Pharmaceuticals, has received consulting fees from Acadia Pharmaceuticals, Alkahest, Aptinyx, Cerevel Therapeutics, the CHDI Foundation, Clintrex LLC (Otsuka), EcoRI Capital, Eisai, Perring, Gray Matter Technologies, Great Lake Neurotechnologies, Intra-Cellular Therapies, Janssen, Merck, Sage, Scion, and Signant Health, and receives license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Time From PD Diagnosis to Site Investigator Dementia Diagnosis in PPMI and Penn Cohorts**
PD = Parkinson disease; Penn = University of Pennsylvania; PPMI = Parkinson's Progression Markers Initiative.

**Figure 2. Estimated Times From PD Diagnosis to Dementia Diagnosis**
Estimated times (A) by age at PD diagnosis in the Penn cohort, (B) by sex in the Penn cohort, and (C) by education level in the Penn cohort (with 95% pointwise confidence limits). PD = Parkinson disease; Penn = University of Pennsylvania.

**Figure 3. Time From Study Enrollment to Dementia Diagnosis for Participants With PD and HCs in the PPMI Cohort**
HC = healthy control; MoCA = Montreal Cognitive Assessment; PD = Parkinson disease; PPMI = Parkinson's Progression Markers Initiative.

See this image and copyright information in PMC

Comment in

Demenz bei Parkinson doch nicht so häufig?
Reichmann H. Reichmann H. MMW Fortschr Med. 2024 Dec;166(21-22):31. doi: 10.1007/s15006-024-4551-6. MMW Fortschr Med. 2024. PMID: 39653909 Review. German. No abstract available.

References

1. Fengler S, Kessler J, Timmermann L, et al. . Screening for cognitive impairment in Parkinson's disease: improving the diagnostic utility of the MoCA through subtest weighting. PLoS One. 2016;11(7):e0159318. doi:10.1371/journal.pone.0159318 - DOI - PMC - PubMed
1. Chahine LM, Weintraub D, Hawkins KA, et al. . Cognition in individuals at risk for Parkinson's: Parkinson associated risk syndrome (PARS) study findings. Mov Disord. 2016;31(1):86-94. doi:10.1002/mds.26373 - DOI - PMC - PubMed
1. Fantini ML, Farini E, Ortelli P, et al. . Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. Sleep. 2011;34(5):619-625. - PMC - PubMed
1. Darweesh SK, Verlinden VJ, Stricker BH, Hofman A, Koudstaal PJ, Ikram MA. Trajectories of prediagnostic functioning in Parkinson's disease. Brain. 2017;140(2):429-441. doi:10.1093/brain/aww291 - DOI - PubMed
1. Darweesh SKL, Wolters F, Postuma R, et al. . Association between poor cognitive functioning and risk of incident parkinsonism: the Rotterdam Study. JAMA Neurol. 2017;74(12):1431-1438. doi:10.1001/jamaneurol.2017.2248 - DOI - PMC - PubMed

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Long-Term Dementia Risk in Parkinson Disease

Collaborators

Affiliation

Long-Term Dementia Risk in Parkinson Disease

Authors

Collaborators

Affiliation

Abstract

Conflict of interest statement

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