Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders. METHODS: We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder. RESULTS: The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5). CONCLUSION: This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.

Psychometric features of Neuropathic Pain Symptom Inventory in Iranian people with Parkinson's disease.

OBJECTIVE: Neuropathic pain is a type of pain reported in people with Parkinson's disease. There are various scales to evaluate the characteristics of this kind of pain. The purpose of this study was to investigate the psychometric properties of the Neuropathic Pain Symptom Inventory (NPSI), a specific scale that measures neuropathic pain in Iranian people with Parkinson's disease. METHOD: Four hundred forty-seven individuals with Parkinson's disease were recruited in the study. Acceptability, internal consistency (Cronbach's alpha), and test-retest reliability (intraclass correlation coefficient, ICC) of NPSI were calculated. Dimensionality was examined through exploratory factor analysis. For convergent validity, correlations of NPSI with Douleur Neuropathic 4, Brief Pain Inventory, King's Pain Parkinson disease Scale, and Visual Analog Scale-Pain were used. Discriminative validity and sensitivity to change between On- and Off- medication states were analyzed. RESULTS: A marked floor effect was observed for this scale (64.2%). Cronbach's alpha and ICC were 0.90 and 0.87, respectively. Items of NPSI were placed in 4 factors. A moderate to the strong association (rs = 0.55 to 0.85) between NPSI and other scales was obtained. The results of discriminative validity and sensitivity to change indicate the ability of NPSI to show differences between medication states. CONCLUSION: The results of this study suggest that NPSI has acceptable reliability, validity, and sensitivity to change, indicating that this scale is suitable for measuring neuropathic pain in Iranian people with Parkinson's disease.

Evolution of prodromal Parkinson's disease and dementia with Lewy bodies: a prospective study.

Parkinson's disease has a long prodromal stage with various subclinical motor and non-motor manifestations; however, their evolution in the years before Parkinson's disease is diagnosed is unclear. We traced the evolution of early motor and non-motor manifestations of synucleinopathy from the stage of idiopathic rapid eye movement (REM) sleep behaviour disorder until defined neurodegenerative disease. During 2004-16, we recruited and then annually followed 154 polysomnography-proven patients with idiopathic REM sleep behaviour disorder, of whom 55 phenoconverted to defined parkinsonism or dementia. Longitudinal data on multiple prodromal features, including the Unified Parkinson's Disease Rating Scale parts I-III, quantitative motor tests, olfaction, colour vision, cognition, and autonomic functions were gathered annually (average = five follow-up visits, range: 2-12 years). The same measures were also assessed in 102 age- and sex-matched healthy control subjects. By looking backward from the time of dementia or parkinsonism diagnosis, we examined trajectories of each prodromal feature using mixed effect models. Based on analysis, olfactory loss was first to develop, with predicted onset >20 years before phenoconversion. This was followed by impaired colour vision, constipation, and erectile dysfunction, starting 10-16 years prior to phenoconversion. At 7-9 years before phenoconversion, slight urinary dysfunction and subtle cognitive decline could be detected. Among motor symptoms altered handwriting, turning in bed, walking, salivation, speech, and facial expression began to be disrupted starting 7-11 years prior to parkinsonism diagnosis, but remained mild until soon before phenoconversion. Motor examination abnormalities began 5-7 years before phenoconversion, with the alternate tap test having the longest interval (8 years before phenoconversion). Among cardinal motor phenotypes, bradykinesia appeared first, ∼5-6 years prior to phenoconversion, followed by rigidity (Year -3) and tremor (Year -2). With direct prospective evaluation of an idiopathic REM sleep behaviour disorder cohort during phenoconversion, we documented an evolution of prodromal manifestations similar to that predicted by pathological staging models, with predicted prodromal intervals as long as 20 years.

Falls in older aged adults in 22 European countries: incidence, mortality and burden of disease from 1990 to 2017.

INTRODUCTION: Falls in older aged adults are an important public health problem. Insight into differences in fall-related injury rates between countries can serve as important input for identifying and evaluating prevention strategies. The objectives of this study were to compare Global Burden of Disease (GBD) 2017 estimates on incidence, mortality and disability-adjusted life years (DALYs) due to fall-related injury in older adults across 22 countries in the Western European region and to examine changes over a 28-year period. METHODS: We performed a secondary database descriptive study using the GBD 2017 results on age-standardised fall-related injury in older adults aged 70 years and older in 22 countries from 1990 to 2017. RESULTS: In 2017, in the Western European region, 13 840 per 100 000 (uncertainty interval (UI) 11 837-16 113) older adults sought medical treatment for fall-related injury, ranging from 7594 per 100 000 (UI 6326-9032) in Greece to 19 796 per 100 000 (UI 15 536-24 233) in Norway. Since 1990, fall-related injury DALY rates showed little change for the whole region, but patterns varied widely between countries. Some countries (eg, Belgium and Netherlands) have lost their favourable positions due to an increasing fall-related injury burden of disease since 1990. CONCLUSIONS: From 1990 to 2017, there was considerable variation in fall-related injury incidence, mortality, DALY rates and its composites in the 22 countries in the Western European region. It may be useful to assess which fall prevention measures have been taken in countries that showed continuous low or decreasing incidence, death and DALY rates despite ageing of the population.

The global burden of falls: global, regional and national estimates of morbidity and mortality from the Global Burden of Disease Study 2017.

BACKGROUND: Falls can lead to severe health loss including death. Past research has shown that falls are an important cause of death and disability worldwide. The Global Burden of Disease Study 2017 (GBD 2017) provides a comprehensive assessment of morbidity and mortality from falls. METHODS: Estimates for mortality, years of life lost (YLLs), incidence, prevalence, years lived with disability (YLDs) and disability-adjusted life years (DALYs) were produced for 195 countries and territories from 1990 to 2017 for all ages using the GBD 2017 framework. Distributions of the bodily injury (eg, hip fracture) were estimated using hospital records. RESULTS: Globally, the age-standardised incidence of falls was 2238 (1990-2532) per 100 000 in 2017, representing a decline of 3.7% (7.4 to 0.3) from 1990 to 2017. Age-standardised prevalence was 5186 (4622-5849) per 100 000 in 2017, representing a decline of 6.5% (7.6 to 5.4) from 1990 to 2017. Age-standardised mortality rate was 9.2 (8.5-9.8) per 100 000 which equated to 695 771 (644 927-741 720) deaths in 2017. Globally, falls resulted in 16 688 088 (15 101 897-17 636 830) YLLs, 19 252 699 (13 725 429-26 140 433) YLDs and 35 940 787 (30 185 695-42 903 289) DALYs across all ages. The most common injury sustained by fall victims is fracture of patella, tibia or fibula, or ankle. Globally, age-specific YLD rates increased with age. CONCLUSIONS: This study shows that the burden of falls is substantial. Investing in further research, fall prevention strategies and access to care is critical.

Mediating effect of mutuality on caregiver burden in Parkinson's disease partners.

Objectives: Parkinson's disease (PD) is a complex neurodegenerative disorder with a broad list of motor and non-motor symptoms (NMS) that has been shown to affect the relationship quality (mutuality) and caregiver burden. However, little is known if the effect of motor and NMS on caregiver burden is mediated by mutuality. Therefore, the aim of this study was to explore if perceived mutuality by patients and partners mediates the effect of motor and NMS on caregiver burden.Methods: Data were collected from 51 dyads with one PD patient, including measures of motor signs, NMS, impaired cognition, patients' and partners' perceived mutuality, caregiver burden and dependency in activities in daily life (ADL). Structural equation model with manifest variables were applied to explore if patients' and partners' mutuality score mediated the effect of motor signs, NMS, ADL or impaired cognition on caregiver burden.Result: Our results suggest that having a partner with PD who is dependent in ADL or has impaired cognition decreases partners' mutuality which leads to elevated burden. Motor symptoms or other NMS were not associated with partners' mutuality or caregiver burden. Instead, increasing severity of motor symptoms decrease patients' mutuality in turn leading to lower level of partners' mutuality.Conclusion: Our findings enhance the understanding of the complexity of living with PD for the partner and suggest that clinical assessment should include evaluation of how PD symptoms influence the quality of the relationship between partners and patients.

A clinical-anatomical signature of Parkinson's disease identified with partial least squares and magnetic resonance imaging.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a wide array of motor and non-motor symptoms. It remains unclear whether neurodegeneration in discrete loci gives rise to discrete symptoms, or whether network-wide atrophy gives rise to the unique behavioural and clinical profile associated with PD. Here we apply a data-driven strategy to isolate large-scale, multivariate associations between distributed atrophy patterns and clinical phenotypes in PD. In a sample of N = 229 de novo PD patients, we estimate disease-related atrophy using deformation based morphometry (DBM) of T1 weighted MR images. Using partial least squares (PLS), we identify a network of subcortical and cortical regions whose collective atrophy is associated with a clinical phenotype encompassing motor and non-motor features. Despite the relatively early stage of the disease in the sample, the atrophy pattern encompassed lower brainstem, substantia nigra, basal ganglia and cortical areas, consistent with the Braak hypothesis. In addition, individual variation in this putative atrophy network predicted longitudinal clinical progression in both motor and non-motor symptoms. Altogether, these results demonstrate a pleiotropic mapping between neurodegeneration and the clinical manifestations of PD, and that this mapping can be detected even in de novo patients.

The burden of headache disorders in the Eastern Mediterranean Region, 1990-2016: findings from the Global Burden of Disease study 2016.

OBJECTIVES: Using the findings of the Global Burden of Disease Study (GBD), we report the burden of primary headache disorders in the Eastern Mediterranean Region (EMR) from 1990 to 2016. METHODS: We modelled headache disorders using DisMod-MR 2.1 Bayesian meta-regression tool to ensure consistency between prevalence, incidence, and remission. Years lived with disability (YLDs) were calculated by multiplying prevalence and disability weight (DW) of migraine and tension-type headache (TTH). We assumed primary headache disorders as non-fatal, so their YLD is equal to disability-adjusted life years (DALYs). RESULTS: Migraine and TTH were the second and twentieth leading causes of YLDs in EMR. Between 1990 and 2016, the absolute YLD numbers of migraine and TTH increased from 2.3 million (95% uncertainty interval (UI): 1.5-3.2) to 4.7 million (95%UI: 3-6.5) and from 383 thousand (95%UI: 240-562) to 816 thousand (95%UI: 516-1221), respectively. During the same period, age-standardised YLD rates of migraine and TTH in EMR increased by 0.7% and 2.5%, respectively, in comparison to a small decrease in the global rates (0.2% decrease in migraine and TTH). The bulk of burden due to headache occurred in the 30-49 year age group, with a peak at ages 35-44 years. The age-standardised YLD rates of both headache disorders were higher in women with female to male ratio of 1.69 for migraine and 1.38 for TTH. All countries of the EMR except for Somalia and Djibouti had higher age-standardised YLD rates for migraine and TTH in compare to the global rates. Libya and Saudi Arabia had the highest increase in age-standardised YLD rates of migraine and TTH, respectively. CONCLUSION: The findings of this study show that primary headache disorders are a major and a growing cause of disability in EMR. Since 1990, burden of primary headache disorders has constantly been higher in EMR compared to rest of the world, which indicates that health systems in EMR must focus further on developing and implementing preventive and management strategies to control headache.

Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression.

Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either ≥1/3 non-motor score >75th percentile, or all three non-motor scores >75th percentile) and 146 as 'intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-ß (329.0 ± 96.7 pg/ml, P = 0.006) and amyloid-ß/total-tau ratio (8.2 ± 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease-specific brain network had more atrophy in the diffuse malignant subtype, with the mild motor-predominant subtype having the least atrophy. Although disease duration at initial visit and follow-up time were similar between subtypes, patients with diffuse malignant Parkinson's disease progressed faster in overall prognosis (global composite outcome), with greater decline in cognition and in dopamine functional neuroimaging after an average of 2.7 years. In conclusion, we introduce new clinical criteria for subtyping Parkinson's disease based on a comprehensive list of clinical manifestations and biomarkers. This clinical subtyping can now be applied to individual patients for use in clinical practice using baseline clinical information. Even though all participants had a recent diagnosis of Parkinson's disease, patients with the diffuse malignant subtype already demonstrated a more profound dopaminergic deficit, increased atrophy in Parkinson's disease brain networks, a more Alzheimer's disease-like cerebrospinal fluid profile and faster progression of motor and cognitive deficits.

Psychometric properties of the Berg balance scale in idiopathic Parkinson' disease in the drug off-phase.

BACKGROUND: Having an appropriate tool for assessment of the balance status during the drug off-phase in idiopathic Parkinson's disease (PD) is relevant for clinical and research settings. Our objective was to assess the clinimetric properties of the Berg balance scale (BBS) during drug off-phase in PD. METHOD: Balance of 98 PD patients (mean age ± SD, 59.19 ± 10.88 years) was evaluated with the BBS. Other assessments in the study included the Fall Efficacy Scale-International (FES-I), Functional Reach Test (FRT), Section II of the Unified Parkinson's Disease Rating Scale-3.0, Parkinson's Disease Questionnaire-39 (PDQ-39), and Schwab and England Activities of Daily Living Scale. All evaluations took place during the drug off-phase. Internal consistency and inter- and intra-rater reliability were evaluated by Cronbach's alpha coefficient and intraclass correlation coefficient, respectively. Dimensionality was explored by factor analysis. Discriminative validity was tested by comparing BBS score between PD patients with and without a history of falling. RESULTS: Internal consistency was high (α = 0.98), as were intra- and inter-rater reliability (ICC = 0.98 and 0.95, respectively). Factor analysis identified only one dimension for the BBS, whose convergent validity with FES-I, FRT, and domain mobility of the PDQ-39 were moderate or high (rS = |0.60-0.74|). Correlation of BBS with functional scales and PDQ-39 Summary Index was moderate (rS = |0.45-0.62|). Finally, the BBS showed a moderate strength to discriminate between PD patients with and without a history of falling. CONCLUSION: Our study suggests that BBS has satisfactory internal consistency, reliability, and construct validity for measuring functional balance in people with PD during the drug off-phase.

Dental care utilization in patients with different types of dementia: A longitudinal nationwide study of 58,037 individuals.

INTRODUCTION: Dementia may be associated with discontinuation of regular dental checkups, which in turn results in poorer oral health. METHODS: We investigated the trend of change in dental care utilization and the number of teeth before and after being diagnosed with dementia. Longitudinal cognitive- and dental health-related information were merged using data on 58,037 newly diagnosed individuals from the Swedish Dementia Registry and Swedish Dental Health Register during 2007 to 2015. RESULTS: Following dementia diagnosis, rate of dental care visits significantly declined. Individuals with mixed dementia, dementia with parkinsonism, and those with more severe and faster cognitive impairment had significantly higher rate of decline in dental care utilization. Vascular dementia and lower baseline Mini-Mental State Examination score were significant predictors of faster loss of teeth. DISCUSSION: Dental care utilization markedly declines following dementia diagnosis. The reduction is more prominent in those with rapid progressive cognitive impairment and the ones with extra frailty burden.

Burden of musculoskeletal disorders in the Eastern Mediterranean Region, 1990-2013: findings from the Global Burden of Disease Study 2013.

OBJECTIVES: We used findings from the Global Burden of Disease Study 2013 to report the burden of musculoskeletal disorders in the Eastern Mediterranean Region (EMR). METHODS: The burden of musculoskeletal disorders was calculated for the EMR's 22 countries between 1990 and 2013. A systematic analysis was performed on mortality and morbidity data to estimate prevalence, death, years of live lost, years lived with disability and disability-adjusted life years (DALYs). RESULTS: For musculoskeletal disorders, the crude DALYs rate per 100 000 increased from 1297.1 (95% uncertainty interval (UI) 924.3-1703.4) in 1990 to 1606.0 (95% UI 1141.2-2130.4) in 2013. During 1990-2013, the total DALYs of musculoskeletal disorders increased by 105.2% in the EMR compared with a 58.0% increase in the rest of the world. The burden of musculoskeletal disorders as a proportion of total DALYs increased from 2.4% (95% UI 1.7-3.0) in 1990 to 4.7% (95% UI 3.6-5.8) in 2013. The range of point prevalence (per 1000) among the EMR countries was 28.2-136.0 for low back pain, 27.3-49.7 for neck pain, 9.7-37.3 for osteoarthritis (OA), 0.6-2.2 for rheumatoid arthritis and 0.1-0.8 for gout. Low back pain and neck pain had the highest burden in EMR countries. CONCLUSIONS: This study shows a high burden of musculoskeletal disorders, with a faster increase in EMR compared with the rest of the world. The reasons for this faster increase need to be explored. Our findings call for incorporating prevention and control programmes that should include improving health data, addressing risk factors, providing evidence-based care and community programmes to increase awareness.

Validation of the MDS research criteria for prodromal Parkinson's disease: Longitudinal assessment in a REM sleep behavior disorder (RBD) cohort.

BACKGROUND: Recently, the International Parkinson and Movement Disorder Society introduced the prodromal criteria for PD. Objectives Our study aimed to examine diagnostic accuracy of the criteria as well as the independence of prodromal markers to predict conversion to PD or dementia with Lewy bodies. METHODS: This prospective cohort study was performed on 121 individuals with rapid eye movement sleep behavior disorder who were followed annually for 1 to 12 years. Using data from a comprehensive panel of prodromal markers, likelihood ratio and post-test probability of the criteria were calculated at baseline and during each follow-up visit. RESULTS: Forty-eight (39.7%) individuals with rapid eye movement sleep behavior disorder converted to PD/dementia with Lewy bodies. The prodromal criteria had 81.3% sensitivity and 67.9% specificity for conversion to PD/dementia with Lewy bodies at 4-year follow-up. One year before conversion, sensitivity was 100%. The criteria predicted dementia with Lewy bodies with even higher accuracy than PD without dementia at onset. Those who met the threshold of prodromal criteria at baseline had significantly more rapid conversion into a neurodegenerative state (4.8 vs. 9.1 years; P < 0.001). Pair-wise combinations of different prodromal markers showed that markers were independent of one another. CONCLUSION: The prodromal criteria are a promising tool for predicting incidence of PD/dementia with Lewy bodies and conversion time in a rapid eye movement sleep behavior disorder cohort, with high sensitivity and high specificity with long follow-up. Prodromal markers influence the overall likelihood ratio independently, allowing them to be reliably multiplied. Defining additional markers with high likelihood ratio, further studies with longitudinal assessment and testing thresholds in different target populations will improve the criteria. © 2017 International Parkinson and Movement Disorder Society.

Early-Onset Dementia: Frequency, Diagnostic Procedures, and Quality Indicators in Three European Tertiary Referral Centers.

BACKGROUND: Early-onset dementia (EOD) is a rare condition, with an often atypical clinical presentation, and it may therefore be challenging to diagnose. Specialized memory clinics vary in the type of patients seen, diagnostic procedures applied, and the pharmacological treatment given. The aim of this study was to investigate quality-of-care indicators in subjects with EOD from 3 tertiary memory clinics in 3 European countries. METHODS: We included 1325 newly diagnosed EOD patients, ages 65 years or younger, between January 1, 2007 and December 31, 2013, from the Danish Dementia Registry (Rigshospitalet, Copenhagen), the Swedish Dementia Registry ("SveDem", Karolinska University Hospital, Stockholm), and the Amsterdam Dementia Cohort (VU University Medical Center). RESULTS: The frequency of EOD among all dementia patients was significantly lower in Copenhagen (410, 20%) and Stockholm (284, 21%) compared with Amsterdam (631, 48%). Not all quality indicator targets were met, such as the time to diagnosis, the mini-mental state examination score available, and the prescription of cholinesterase inhibitors. Cerebrospinal fluid sampling, registered in 2 sites, was performed in over 80% of the subjects. CONCLUSIONS: In tertiary referral centers in Copenhagen, Stockholm, and Amsterdam, quality indicators were not always met for patients with EOD. Results partly reflect differences in referral pattern, the application of diagnostic criteria, and local best practices. Standardized international procedures for patients with EOD may reduce this variability.

Subtypes of Parkinson's Disease: What Do They Tell Us About Disease Progression?

Parkinson's disease is a widely heterogeneous disorder with a broad list of motor and nonmotor manifestations. Identifying subtypes of Parkinson's disease is one of the top clinical and research priorities. This review aims to summarize the most valid conventional and recent subtyping solutions that have been introduced so far and to update our current knowledge with recent discoveries on the association between subtypes and disease progression. We also discuss the challenges of subtyping in the context of Parkinson's disease, stability of the subtypes over time, and potential clinical implications. Sophisticated evidence show that there are distinct subtypes of Parkinson's disease with diverging trends of progression. A more holistic view of subtyping to merge traditional motor features with key nonmotor manifestations is a promising approach to identify subgroups with different prognosis. Subtyping could improve further by adding continuing to add data from imaging, CSF, and genetic biomarkers.