A Call for Change: Updating the Operational Definition for Dementia in Parkinson's Disease

In Parkinson's disease (PD), cognitive dysfunction ranges from subjective cognitive complaints to mild cognitive impairment (PD-MCI) and PD dementia (PDD). Timely identification and management of cognitive impairment are major challenges in PD, with substantial burdens on those affected and healthcare systems.1 Recognizing the need for criteria for different stages of cognitive impairment in PD, the Movement Disorder Society (MDS) commissioned task forces developed clinical diagnostic criteria for PDD2 (2007) and PD-MCI3 (2012) to identify cognitive impairments and ensure uniform participant criteria for therapeutic trials. The criteria, based on literature review and expert consensus, provide recommendations for diagnostic procedures that operationalize PDD4 and PD-MCI3 diagnoses and allow for Level I and II assessments (depending on available time and resources), which have both undergone formal validation.5, 6 The PD-MCI criteria have not only advanced the field regarding clinical, biomarker, genetic features and the conversion to PDD, but also facilitated pathways for industry and regulatory authorities to conduct clinical trials, specifically addressing this “at risk” stage of cognitive impairment.7 At the time when the PDD criteria were established, however, there was still considerable influence from the Alzheimer's disease (AD) field and few robust biomarkers. Indeed, the only symptomatic medication approved by regulatory authorities for PDD (namely rivastigmine) used the ADAS-cog, as the primary outcome measure.8 Even recent PDD trials vary substantially in their inclusion criteria and outcome measures selected, making reliable comparisons among studies or conducting meta-analyses nearly impossible. Since the publication of the PDD criteria, considerable progress has been made in understanding the course and causes of cognitive deterioration in PD, along with the evolution of biofluid and imaging biomarkers.9 Clinically, this progress includes a greater appreciation of behavioral complications that often accompany cognitive progression, as well as the heterogeneity of PD cognitive phenotypes and differing trajectories. Technological advances now offer computerized, smartphone and online assessments, providing novel approaches for assessing neuropsychological and functional abilities.10 Subgroups at higher risk of progressing to PDD have been identified from genetic risk factors and associated clinical features, such as Rapid Eye Movement Sleep Behavior Disorder (RBD) and motor phenotype.11 It is now recognized that cognitive impairment can begin in the prodromal and early phases of PD with many patients satisfying diagnostic criteria for PD-MCI at the time of PD diagnosis. The recognition of prodromal cognitive impairment, prior to or after motor symptom onset, has blurred the diagnostic boundaries between PD12 and dementia with Lewy bodies (DLB),13-15 with added challenges of defining prodromal PD16 and prodromal DLB,17 and PD-MCI and DLB-MCI.18 Whether these observations and the emergence of diagnostic biomarkers of alpha-synuclein (eg, alpha-synuclein seed amplification assay [a-syn SAA]), dopaminergic neuron dysfunction, or neurodegeneration as proposed in recent biological frameworks will unify PD and DLB as a single diagnostic entity remains to be seen, but these distinctions further highlight the need to go beyond our existing diagnostic framework that was developed more than 15 years ago. Considerable progress has been made in developing neurodegenerative biomarkers (eg, in vivo assays with biofluids, tissues, imaging) that reflect putative underlying pathobiology. Utilization of accurate biomarkers that allow for disease-modifying therapies to be introduced at the earliest time point is a desired strategy, and the development of a biological diagnosis for AD based on amyloid, tau, and neurodegeneration biomarkers now allows for such treatments to enter clinical practice.19 Recent development of a-syn SAAs offer promise for biologically defining PD,20, 21 although these tests may be limited by their specificity and binary outcomes.22 Novel biomarkers may improve diagnostic accuracy, and emerging data suggests that some quantitative parameters of a-syn SAA may help in predicting future cognitive decline.23 However, these biomarkers will not currently help clinicians or researchers to determine the presence or severity of cognitive impairment in PD patients. Thus, we will still require accurate methods of distinguishing those “at risk” individuals with PD-MCI and clear clinical guidance to establish the transition to PDD. Future studies may elucidate integrated approaches for biological and clinical frameworks that encompass the PD cognitive spectrum. While AD and PD differ in many ways, the evolution of AD diagnostic criteria serve to emphasize that the PD field needs to consider criteria, such as for PDD, as frameworks to be updated in response to scientific advances. Thus, in keeping with revisions to AD diagnostic criteria19 and clinical and biological advances in PD, we believe that it is timely to revisit the PDD criteria and establish a pathway for updating new criteria. Revised criteria would both facilitate the comparability of different studies and provide clear regulatory pathways for therapeutics. Dementia should develop after the onset of clinical PD Include alpha-synuclein seed assay testing and recently proposed biological classifications/ definitions for PD Explore whether to adapt the criteria for cognitive domain impairments. Consider whether to modify cut-off points or include “single-domain dementia” (eg, a single domain that significantly impairs ADL). The current diagnostic criteria for PDD consider structural and functional neuroimaging, electroencephalography, event-related potentials, cardiac scintigraphy and genetic testing. As noted, it is possible that a-syn SAA could help to more reliably identify synucleinopathy and potentially predict future cognitive decline,23 but these investigations will still need to be correlated with clinical findings. Clinical and research use of AD biomarkers for diagnosis is now commonplace37 and relevant to the PDD criteria, given that AD co-pathology present in PD confers a more aggressive cognitive decline.38 Other biomarkers like serum neurofilament light chain may, in the future, serve as proxies for rates of neurodegeneration.39 Neuroimaging advances in resting state functional MRI, neuromelanin, quantitative susceptibility mapping, free water imaging and cholinergic PET may merit further consideration.40 Finally, the impact of genetics on cognitive decline in PD (eg, GBA, APOE4 and microtubule-associated protein tau (MAPT)) may need to be factored into future assessments for PDD.11 The current expansion of disease-modifying trials and therapeutic approaches specifically targeting PDD underscores the urgent need for revised criteria that can be used in research trials. This initiative will require wide consultation with stakeholders including those with lived experience (people with PDD, care partners) to understand how key topics such as definitions of PDD, use of biomarkers, relative timing of cognitive decline and parkinsonian motor features, severity of cognitive impairment required for PDD diagnosis, and functional impact may influence their perceptions and participation in research trials. We propose that the MDS should convene a Task Force to conduct a staged approach to revising the PDD criteria. The first stage would include a thorough review of relevant literature since the 2007 PDD criteria publication, which would lead to a consensus statement addressing the scope of the revision required. The second stage would be to produce revised PDD diagnostic criteria with recommendations for abbreviated and comprehensive (including biomarker) assessments. Conducting a critical review of the diagnosis and staging of dementia in PD, leading to an updated, consistent, and unified definition, will not only provide clarity, consistency and a common framework for understanding and discussing how cognition worsens at different stages and timepoints in PD, but also facilitate accurate and timely diagnoses, effective treatment, research advancements, public awareness and appropriate policy planning to benefit our patients. (1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique. (3) Manuscript: A. Writing of the first draft, B. Review and Critique. J.K.: 3A, 3B. I.L.: 3B. D.W.: 3B. J.G.G.: 3B. A.I.T.: 3B. S.J.G.L.: 3B. Funding Sources and Conflict of Interest: This manuscript was not supported by any specific funding and the authors declare no relevant conflicts of interest. Financial Disclosures for the Previous 12 Months: DW has received research funding or support from Michael J. Fox Foundation for Parkinson's Research, Alzheimer's Therapeutic Research Initiative (ATRI), Alzheimer's Disease Cooperative Study (ADCS), International Parkinson and Movement Disorder Society (IPMDS), National Institute on Health (NIH), The Parkinson's Foundation and the U.S. Department of Veterans Affairs; honoraria for consultancy from Alkahest, Aptinyx, Boehringer Ingelheim, Cerevel Therapeutics, CHDI Foundation, CuraSen, Ferring, Medscape, Modality. AI, Roche, Sage, Scion, Signant Health and Takeda; and license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS. Dr. Kulisevsky is supported by CIBERNED and FIS PI2022 (Carlos III, Institute); AGAUR (Agència de Gestió d'Ajuts Universitaris i de Recerca, Generalitat de Catalunya); received compensation for lectures or advise from Zambon, Abvvie, AC Immune, Roche, UCB, Esteve, and BIAL. He receives his salary from Hospital de Sant Pau and Universitat Autònoma de Barcelona. IL's research is supported by the National Institutes of Health grants: U01NS100610, 2R01 AG063911, 1R61 NS141119-01, 2 P30 AG062429-06 and 1R21NS114764-01A1; the Michael J. Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Lundbeck, EIP-Pharma, Novartis, Alterity and UCB. She is a member of the Scientific Advisory Board for Amydis, the Rossy PSP Program at the University of Toronto and Aprinoia. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. JGG has received research funding from Acadia, Lewy Body Dementia Association, and Michael J. Fox Foundation. She has received compensation from EIP Pharma, GE Healthcare, InMune Bio, PaxMedica, Roche, and SAGE. She has received honoraria from the International Parkinson and Movement Disorder Society, Lewy Body Dementia Association, Parkinson Study Group, and Parkinson's Foundation. AIT receives his salary from Dignity Health and receives research support from the Barrow Neurological Foundation. He receives a stipend from the International Neuropsychological Society as Associate Editor of the Journal of the International Neuropsychological Society (JINS) and royalties from Oxford University Press. SJGL is supported by a National Health and Medical Research Council Leadership Fellowship (1195830) and has received research funding from the Michael J. Fox Foundation and the Australian Research Council, as well as consulting for Pharmaxis Ltd. Ethical Compliance Statement: No ethics committee or IRB was required for the approval of this Viewpoint article and informed consent was not necessary. The authors confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Charles Adler, Guido Alves, Paolo Amami, Tim Anderson, Roger Barker, Paolo Barone, Ondrej Bezdicek, Roberta Biundo, David Breen, David Burn, Marta Camacho, Davide Cammisuli, James Caviness, Rosca Cecilia, Brenna Cholerton, John Dalrymple-Alford, Rob de Bie, Sarah Duff-Canning, Paul Eslinger, Matthew Farrer, Carmen Gasca-Salas, Gert Geurtsen, Steven Gunzler, Glenda Halliday, Xuemei Huang, Naroa Ibarretxe Bilbao, James Leverenz, Connie Marras, Elie Matar, Brit Mollenhauer, Carme Junque, Kenn Pedersen, Lucia Ricciardi, Mari Rodríguez-Oroz, Gabriella Santangelo, Dawn Schiehser, Bàrbara Segura, Rimona Weil, Caroline Williams-Gray, Ruey-Meei Robin Wu, Alison Yarnall, Rwei-Ling Yu, Cyrus Zabetian. Not applicable.

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