P.015 Long-term progression and prognosis in different subtypes of Parkinson’s disease: validation of a new multi-domain subtyping method

Background: Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods: Data on 421 individuals with de novo early-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results: Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions: This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.

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Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202127 ◽

2020 ◽

Vol 10 (4) ◽

pp. 1541-1549

Author(s):

Seok Jong Chung ◽

Sangwon Lee ◽

Han Soo Yoo ◽

Yang Hyun Lee ◽

Hye Sun Lee ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Early Stage ◽

Striatal Dopamine ◽

Motor Deficits ◽

Dopamine Depletion ◽

Severe Motor ◽

Severe Group ◽

Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

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Sex Differences in Cognitive Changes in De Novo Parkinson’s Disease

Journal of the International Neuropsychological Society ◽

10.1017/s1355617719001085 ◽

2019 ◽

Vol 26 (2) ◽

pp. 241-249 ◽

Cited By ~ 1

Author(s):

Ece Bayram ◽

Sarah J. Banks ◽

Guogen Shan ◽

Nikki Kaplan ◽

Jessica Z.K. Caldwell

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Sex Differences ◽

Verbal Memory ◽

Healthy Aging ◽

De Novo ◽

Cognitive Changes ◽

Progression Markers ◽

Cognitively Intact

AbstractObjective:To evaluate the sex differences in cognitive course over 4 years in Parkinson’s disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls.Methods:Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson’s Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared.Results:Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period).Conclusions:Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

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Brain Grafting as a Treatment for Parkinson's Disease

Neurosurgery ◽

10.1227/00006123-198702000-00026 ◽

1987 ◽

Vol 20 (2) ◽

pp. 335-342 ◽

Cited By ~ 21

Author(s):

Mark J. Perlow

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Manifestations ◽

Dopamine Neurons ◽

Clinical Aspects ◽

Pathological Changes ◽

Pharmacological Treatments ◽

The Central Nervous System ◽

The Brain

Abstract Parkinson's disease is an illness with neuropathological and neuroanatomical abnormalities in many areas of the central nervous system. Some clinical manifestations of this illness are correlated with pathological changes in the substantia nigra and with a loss of dopamine in the nigra and striatum. The most effective pharmacological treatments have used agents that either replace the lost dopamine or act as agonists on dopamine receptors. Recent studies in animal models of Parkinson's disease demonstrate that the loss of dopamine and many clinical manifestations of dopamine reduction can be reversed by transplantation of fetal dopamine-containing cells to specific dopamine-depleted areas of the brain. Long term viability of these transplants has also been demonstrated. The author suggests that the transplantation of dopamine neurons, even across species barriers, is a reasonable consideration for the treatment of human Parkinson's disease. This article reviews in detail the results of recent experiments and how the experience in these models might be utilized in determining a transplantation strategy for the treatment of specific clinical aspects of this illness.

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A clinical-anatomical signature of Parkinson’s Disease identified with partial least squares and magnetic resonance imaging

10.1101/168989 ◽

2017 ◽

Cited By ~ 3

Author(s):

Yashar Zeighami ◽

Seyed-Mohammad Fereshtehnejad ◽

Mahsa Dadar ◽

D. Louis Collins ◽

Ronald B. Postuma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Least Squares ◽

Partial Least Squares ◽

Large Scale ◽

De Novo ◽

Neurodegenerative Disorder ◽

Clinical Manifestations ◽

Motor Symptoms ◽

Non Motor Symptoms

AbstractParkinson’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.

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Virtual Exam for Parkinson's Disease Enables Frequent and Reliable Measurements of Motor Function

10.1101/2021.12.22.21268260 ◽

2021 ◽

Author(s):

Maximilien Burq ◽

Erin Rainaldi ◽

King Chung Ho ◽

Chen Chen ◽

Bastiaan R Bloem ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Stage ◽

Real Life ◽

Dropout Rate ◽

Therapeutic Interventions ◽

Retest Reliability ◽

Time Sensitivity ◽

Remote Measurements ◽

Test Retest Reliability

Sensor-based remote monitoring could help us better track Parkinson's disease (PD) progression, and measure patients' response to putative disease-modifying therapeutic interventions. To be useful, the remotely-collected measurements should be valid, reliable and sensitive to change, and people with PD must engage with the technology. We developed a smartwatch-based active assessment that enables unsupervised measurement of motor signs of PD. 388 study participants with early-stage PD (Personalized Parkinson Project, 64% men, average age 63 years) wore a smartwatch for a median of 390 days, allowing for continuous passive monitoring. Participants performed unsupervised motor tasks both in the clinic (once) and remotely (twice weekly for one year). Dropout rate was 2% at the end of follow-up. Median wear-time was 21.1 hours/day, and 59% of per-protocol remote assessments were completed. In-clinic performance of the virtual exam verified that most participants correctly followed watch-based instructions. Analytical validation was established for in-clinic measurements, which showed moderate-to-strong correlations with consensus MDS-UPDRS Part III ratings for rest tremor (R=0.70), bradykinesia (R=-0.62), and gait (R=-0.46). Test-retest reliability of remote measurements, aggregated monthly, was good-to-excellent (ICC: 0.75 - 0.96). Remote measurements were sensitive to the known effects of dopaminergic medication (on vs off Cohen's d: 0.19 - 0.54). Of note, in-clinic assessments often did not reflect the patients' typical status at home. This demonstrates the feasibility of using smartwatch-based unsupervised active tests, and establishes the analytical validity of associated digital measurements. Weekly measurements can create a more complete picture of patient functioning by providing a real-life distribution of disease severity, as it fluctuates over time. Sensitivity to medication-induced change, together with the improvement in test-retest reliability from temporal aggregation implies that these methods could help reduce sample sizes needed to demonstrate a response to therapeutic intervention or disease progression.

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Predicting the onset of freezing of gait in de novo Parkinson’s disease

10.1101/2021.03.11.21253192 ◽

2021 ◽

Author(s):

Fengting Wang ◽

Yixin Pan ◽

Miao Zhang ◽

Kejia Hu

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Freezing Of Gait ◽

Poor Quality ◽

Csf Biomarkers ◽

Genetic Characteristics ◽

Progression Markers ◽

Independent Risk Factors

AbstractFreezing of gait (FoG) is a debilitating symptom of Parkinson’s disease (PD) related to higher risks of falls and poor quality of life. In this study, we predicted the onset of FoG in PD patients using a battery of risk factors from patients enrolled in the Parkinson’s Progression Markers Initiative (PPMI) cohort. The endpoint was the presence of FoG, which was assessed every year during the five-year follow-up visit. Overall, 212 PD patients were included in analysis. Seventy patients (33.0%) developed FoG during the visit (pre-FoG group). Age, bradykinesia, TD/PIGD classification, fatigue, cognitive impairment, impaired autonomic functions and sleep disorder were found to be significantly different in patients from pre-FoG and non-FoG groups at baseline. The logistic regression model showed that motor factors such as TD/PIGD classification (OR = 2.67, 95% CI = 1.41-5.09), MDS-UPDRS part III score (OR = 1.05, 95% CI = 1.01-1.09) were associated with FoG occurrence. Several indicators representing non-motor symptoms such as SDMT total score (OR = 0.95, 95% CI = 0.91-0.98), HVLT immediate/Total recall (OR = 0.91, 95% CI = 0.86-0.97), MOCA (OR = 0.87, 95% CI = 0.76-0.99), Epworth Sleepiness Scale (OR = 1.13, 95% CI = 1.03-1.24), fatigue(OR = 1.98, 95% CI = 1.32-3.06), SCOPA-AUT gastrointestinal score (OR = 1.27, 95% CI = 1.09-1.49) and SCOPA-AUT urinary score (OR = 1.18, 95% CI = 1.06-1.32) were found to have the predictive value. PD patients that developed FoG showed a significant reduction of DAT uptake in the striatum. However, no difference at baseline was observed in genetic characteristics and CSF biomarkers between the two patient sets. Our model indicated that TD/PIGD classification, MDS-UPDRS total score, and Symbol Digit Modalities score were independent risk factors for the onset of FoG in PD patients. In conclusion, the combination of motor and non-motor features including the akinetic subtype and poor cognitive functions should be considered in identifying PD patients with high risks of FoG onset.

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Network structure of brain atrophy in de novo Parkinson's disease

eLife ◽

10.7554/elife.08440 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 97

Author(s):

Yashar Zeighami ◽

Miguel Ulla ◽

Yasser Iturria-Medina ◽

Mahsa Dadar ◽

Yu Zhang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Medial Temporal Lobe ◽

Healthy Aging ◽

De Novo ◽

Progression Markers ◽

Magnetic Resonance Imaging Mri ◽

Cortical Regions ◽

Clinical Measures ◽

Deformation Based Morphometry

We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation.

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