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Markers For Parkinson’s Disease

Simple Blood Test Could Help Predict Progression Of Parkinson’s Disease

Biomarkers for Parkinson’s Disease | 2019 Udall Center Research Symposium
Date:
IOS Press
Summary:
In order to provide the best medical care for newly diagnosed Parkinson’s disease patients, a method of predicting their cognitive and motor progression, beyond using purely clinical parameters, would have major implications for their management.

In order to provide the best medical care for newly diagnosed Parkinson’s disease patients, a method of predicting their cognitive and motor progression, beyond using purely clinical parameters, would have major implications for their management. A novel study published in the Journal of Parkinson’s Disease suggests that a blood test for inflammatory and cell senescence biomarkers may be a reliable predictor of cognitive decline, including identifying those who will develop an early dementia and motor progression in PD patients.

Investigators examined the association of blood-derived markers with motor and cognitive function over time to discover if this could help to better predict disease progression of newly diagnosed PD patients. More than 150 newly diagnosed PD patients who participated in the Cognitive Impairments in Cohorts with Longitudinal Evaluation-Parkinson’s Disease study and 99 controls underwent physical and cognitive assessments over 36 months of follow-up.

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Rna Isolation And Quality Control

Venous blood was collected in PAXgene tubes and immediately incubated at room temperature for 24 h. RNA was then extracted after the PAXgene procedure including DNase treatment. RNA quality was determined by spectrophotometry and by using the RNA 6000 NanoChip kit on an Agilent 2100 Bioanalyzer . RNA passing quality control criteria were used for further analysis.

Blood Collection And Processing

Blood samples were collected per participant by venipuncture into three EDTA-containing tubes. To isolate the erythrocytes, freshly drawn blood was centrifuged at 2000 g at 4°C. Erythrocytes were washed 3 times with Phosphate Buffered Saline , followed by 10min centrifugation at 2000 g at 4°C. Erythrocytes were stored at 80°C until further use.

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Cohort : Relation Between 4

An inverse association was found between relative changes over 4 years in free water in PSN and relative changes over 4 years in SBR in the putamen , but not between changes in free water and changes in SBR in the caudate .

Correlation plot illustrating the relation between 4-year relative per cent change in free water in PSN and 4-year relative per cent change in SBR in the putamen. FW = free water PUT = putamen.

The results of the power analyses based on free water in PSN and SBR in the putamen are shown in . Briefly, the power analysis for a two-arm study using relative change in free water in PSN over 2 years as an outcome measure indicated that to detect a significant effect of a neuroprotective agent with 90% power and 50% predicted change, 176 subjects are required across groups. When assuming a 70% effect of a drug, the sample estimate for 2-year changes in free water in PSN at 90% power is 90 subjects. provides additional sample size estimations for 4-year changes in free water, and 2- and 4-year changes in SBR in the putamen.

Patient Population And Demographics

sf inhibited loss of parkinsons disease pd related

We recruited a group of 88 individuals, divided into 3 subgroups: 28 diagnosed with PD for 24 years, 30 diagnosed for 10 years, and 30 controls. Blood samples were processed by the same personnel. The PD group diagnosed with the disease for 24 years presented a male to female ratio of 1: 1, a mean age at onset of 69.0±10.3 years, a mean disease duration of 3.1±0.7 years, a MDS-UPDRS III of 38.4±10.8 and a HY of 1.6±0.8. The PD group diagnosed for 10 years presented a M:F ratio of 1: 1, a mean age of onset of 67.2±7.6 years, a mean disease duration of 17.7±4.3, a MDS-UPDRS III of 60.0±19.9 and a HY of 3.0±1.1. The mean age of controls was 67.2±7.6 years. Male to female ratio in the control group was 1:2 .

Table 1 Demographics data of recruited individuals.

Importantly, although the levodopa equivalent daily dose was significantly higher in the patients diagnosed for 10 years , LEDD did not correlate with the levels of PTMs .

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What Is The Parkinson’s Progression Markers Initiative

The Parkinsons Progression Markers Initiative is a longitudinal research study aiming to identify biomarkers of Parkinsons disease and its progression. The study is led by the Michael J. Fox Foundation for Parkinsons Research, and Verily joined as a research partner in 2018. This is one of two longitudinal Parkinsons research programs that Verily is supporting. The other is the Personalized Parkinson’s Project.

Positron Emission Tomography Scan

The PET scan radiotracers emit electron anti-particles that are positively charged with the same mass as an electron. The presence of presynaptic DAT in dopaminergic neurons of striatum and SN can be assessed with 18F and/or 11C radiolabeled dopamine analogs. These DAT radioligands include 18F-dopamine , 18F-FE-PE2I , 18F–CFT , 18F-LBT999 , and11C-methylphenidate. The VMAT2 quantification is also possible by using either 11C or 18F radiolabeled dihydrotetrabenazine . Because of dopaminergic cell loss and subsequent loss of VMAT2, the PET signal of radiolabeled DTBZ is lower in PD patients than in controls. Both DAT and VMAT2 radioligands can detect the early signs of dopaminergic damage, although PD may not be differentiated from atypical Parkinsonism with dopaminergic dysfunction. 11C-MP4A is another PET radiotracer that monitors the level of acetylcholinesterase activity. AChE hydrolyses deactivates Ach and terminates the signal. Impairment of cholinergic system and reduction of cortical AChE has been assessed by 11C-MP4A-PET scan. AChE activity reduces more in PDD than in PD, indicating that cholinergic dysfunction is correlated with dementia in PD .

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Conflict Of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling Editor declared a shared affiliation, though no other collaboration, with one of the authors and states that the process nevertheless met the standards of a fair and objective review.

Identification Of A Molecular Signature Of Pd In Blood

NINDS Parkinsons Disease Biomarkers Program Enrolls 1,000th Patient

To identify a transcriptional profile associated with PD we probed RNA extracted from whole blood of 50 PD patients predominantly at early disease stages and 55 age-matched controls with 22,283 oligonucleotide probe sets on microarrays. The disease controls included patients with AD that may be misclassified as PD , as well as with progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration, which closely mimic the clinical features of PD but differ in etiology, prognosis, and treatment response. We carefully assayed for shifts in differential blood counts that could bias gene expression changes and found no significant difference between PD and controls .

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Genetic Forms And Genetic Risk Factors Of Pd

Although most cases of PD are idiopathic forms of the disease, about 15% of PD patients are recognized as having a first-degree family member with this disease. Recently, the genetic factors and gene loci involving in autosomal dominant and autosomal recessive forms of PD have been discovered due to advanced molecular genetics . The mutations in several genes, including -syn, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1 are linked to PD . In addition to mutations in these genetic loci, polymorphisms, and trinucleotide repeats are recognized as PD genes, or susceptibility factors for PD .

Section Ii Award Information

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

The OER Glossary and the SF424 Application Guide provide details on these application types.

NIH intends to fund an estimate of 5-7 awards, corresponding to a total of $5,000,000 , for fiscal year . Future year amounts will depend on annual appropriations.

  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

  • Hispanic-serving Institutions
  • Historically Black Colleges and Universities
  • Tribally Controlled Colleges and Universities
  • Alaska Native and Native Hawaiian Serving Institutions
  • Asian American Native American Pacific Islander Serving Institutions

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501 IRS Status
  • Nonprofits without 501 IRS Status

For-Profit Organizations

  • For-Profit Organizations

Governments

  • Indian/Native American Tribal Governments
  • Indian/Native American Tribal Governments
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations
  • Faith-based or Community-based Organizations
  • Non-domestic Entities

are are

2. Cost Sharing

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Epigenetic Risk Factors Of Pd

Epigenetics refer to chromatin alternations, including DNA methylation and histone post translational modifications that can alter gene expression without changes in DNA sequence. These modifications can be inherited, but environmental factors including nutritional, chemical and physical factors can also affect epigenetics . In sporadic form of PD involvement of environmental factors in initiation and progression of disease emerging an idea that epigenetic plays an important role in PD . One of the examples of epigenetic mechanism in PD is modification of -syn gene . SNCA has two CpG islands with the first one being located in exon 1 and the second one within intron 1. Transcription factors GATA and ZSCAN21 bind to the intron 1 CpG-2 island and modulate transcription of -syn. CpG-2 methylation prevents the binding of the TFs to SNCA and subsequently inhibits the overexpression of -syn. Interestingly, binding of transcription factors to -syn and another member of the synuclein family, -synuclein , has been described, suggesting that synuclein family members are involved in various complex mechanisms of gene expression regulation. Therefore, their role in PD is not limited to the formation of toxic aggregates, but may be complemented by participation in regulatory processes.

Limitations In Studies On Prodromal Markers In Pd

Advances in markers of prodromal Parkinson disease ...

Study Design

Five studies showed limitations in study design and three conventional case-control studies ). The other studies were prospective cohort studies , or nested case-control studies .

No Inclusion/Exclusion Criteria

No study showed a total lack of inclusion or exclusion criteria. However, criteria differed between studies dependent on the data source and on study-specific inclusion/exclusion criteria as relevant for marker assessments and PD diagnosis.

Drop-Outs

No study reported a drop-out rate of over 20% between baseline and last follow-up without investigating factors associated with the drop-out to exclude a potential drop-out bias.

Insufficient Sample Size

Three studies did not fulfill the criterion of sufficient sample size. Two prospective cohorts with < 50, and one case-control study with < 100 participants at baseline.

No Report of Marker Associations

No study failed to report statistical effects or detailed descriptive statistics.

Reduced Validity of PD Diagnosis

Limitations in Prodromal Marker Assessments

Eighteen studies showed limitations in prodromal marker assessments. Marker information was based on questionnaires/self-reports in 13 studies with 2 studies using longer term retrospective self-reports with possible recall bias, and was based on medical records in five studies .

Reduced Generalizability of Findings

Findings of six studies might not be generalizable to females as only males were investigated.

Limitations of Statistical Analyses

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Molecular Markers Of Early Parkinson’s Disease Based On Gene Expression In Blood

  • *Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, MA 02139
  • Neurology Service, Massachusetts General Hospital, Boston, MA 02114
  • Partners Parkinson and Movement Disorders Center, Boston, MA 02114
  • ¶Center for Human Genetics, Duke University Medical Center, Durham, NC 27710 and
  • Department of Physics, University of Massachusetts, Boston, MA 02125
  • See allHide authors and affiliations

      What Doctors Look For When Diagnosing Parkinsons

      Certain physical signs and symptoms noticed by the patient or his or her loved ones are usually what prompt a person to see the doctor. These are the symptoms most often noticed by patients or their families:

      • Shaking or tremor: Called resting tremor, a trembling of a hand or foot that happens when the patient is at rest and typically stops when he or she is active or moving

      • Bradykinesia: Slowness of movement in the limbs, face, walking or overall body

      • Rigidity: Stiffness in the arms, legs or trunk

      • Posture instability: Trouble with balance and possible falls

      Once the patient is at the doctors office, the physician:

      • Takes a medical history and does a physical examination.

      • Asks about current and past medications. Some medications may cause symptoms that mimic Parkinsons disease.

      • Performs a neurological examination, testing agility, muscle tone, gait and balance.

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      Convolutional Neural Nets With Discriminative Localization

      CNNs are a modern adaption of the traditional artificial neural network architecture where millions of 2D convolutional filter parameters are computed from multiple levels of granularity and transformed into the desired output by end-to-end optimization. The CNN can therefore be considered as an automated feature extraction tool with a classifier in the final stages.

      The figure displays a schematic diagram of the CNN architecture. ResNet50 architecture was employed with 16 blocks . The class activation maps were computed using global average pooling as shown in the figure.

      Throughout the CNN architecture, we employ rectified linear unit activations and with a learning rate of 0.0001 which decays based on the number of iterations. The weights of each of layers are updated to train the complete CNN model by minimizing the categorical cross entropy loss function as given in equation 1 where yn is target output probability, is predicted output probability, N is number of testing samples and J is categorical cross-entropy loss, and is achieved by using the Adam optimizer. Finally, to reduce the susceptibility to over-fitting, as a standard practice, data augmentation was performed which increased the dataset by several folds.

      Autonomic Dysfunctions In Parkinsons Disease: Prevalence Clinical Characteristics Potential Diagnostic Markers And Treatment

      Ask the MD: Parkinson’s Diagnosis and Biomarkers

      Sheng-Di Chen

      1Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

      2Department of Neurology, Peking Union Medical College Hospital, Beijing, China

      Abstract

      Parkinsons disease is a common neurodegenerative disease in the middle-aged and the elderly. Symptoms of autonomic dysfunctions are frequently seen in PD patients, severely affecting the quality of life. This review summarizes the epidemiology, clinical manifestations, and treatment options of autonomic dysfunctions. The clinical significance of autonomic dysfunctions in PD early diagnosis and differential diagnosis is also discussed.

      1. Introduction

      In this review, we will discuss the prevalence, clinical manifestations, and treatment of autonomic dysfunctions in PD, as well as the clinical significance of autonomic dysfunctions in early diagnosis and differential diagnosis of PD.

      2. Prevalence of Autonomic Dysfunctions in PD

      About 27% to 39% PD patients had symptoms of urinary system dysfunctions, which could be categorized into irritative and obstructive symptoms . The incidence of detrusor hyperreflexia was as high as 45 to 100%, while the incidence of obstructive symptoms was 27% .

      3. Clinical Manifestations of Autonomic Dysfunctions in PD

      3.1. Autonomic Dysfunctions of Cardiovascular System
      3.2. Autonomic Dysfunctions of Gastrointestinal System
      3.3. Autonomic Dysfunctions of Urinary System
      3.4. Autonomic Dysfunctions of Reproductive System

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      Training And Testing Of The Models

      The dataset was randomly divided into training and testing while retaining the PD:HC ratio in both the classes. We used, 25 healthy controls and 30 PD subjects for training and crossvalidating the models and the remaining 10 HCs and 15 PD patients for testing the models. The receiver operation characteristics , accuracy, F1-score, precision and recall were computed on the cross-validation and test dataset and reported.

      Dopamine Dopamine Receptor And Dopamine Transporter Activity

      A catecholamine neurotransmitter dopamine is secreted by the SN, hypothalamus and some other regions of the brain. TH synthesizes the dopamine precursor that is converted to dopamine by L-aromatic amino acid decarboxylase . In the brain, dopamine is used as the precursor of noradrenaline and adrenaline . Loss of dopaminergic neurons in the midbrain and SN of PD brains leads to the reduction of dopamine levels . The dopamine transporter controls dopamine levels by facilitating its reuptake back to the cytosol. However, free dopamine is toxic for neurons, since its oxidation creates poisonous reactive quinones. Therefore, the vesicular monoamine transporter 2 stores excess dopamine in vesicles. Thus, any change in dopamine or DAT levels may be an indicator of PD. Moreover, dopamine activates five types of receptors and the severity of PD is related to the decreased expression of the dopamine type 3 receptor , leading to more severe symptoms because of reduced dopamine signals . Therefore, D3R can be also considered as a potential biomarker for PD .

      In another recent article a preclinical phase of PD is identified by analysis of dopamine metabolites in CSF. Low CSF concentrations of 3,4-dihydroxyphenylacetic acid and DOPA identify pre-clinical PD in at-risk healthy individuals .

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      Is Early Diagnosis Possible

      Experts are becoming more aware of symptoms of Parkinsons that precede physical manifestations. Clues to the disease that sometimes show up before motor symptoms and before a formal diagnosis are called prodromal symptoms. These include the loss of sense of smell, a sleep disturbance called REM behavior disorder, ongoing constipation thats not otherwise explained and mood disorders, such as anxiety and depression.

      Research into these and other early symptoms holds promise for even more sensitive testing and diagnosis.

      For example, biomarker research is trying to answer the question of who gets Parkinsons disease. Researchers hope that once doctors can predict that a person with very early symptoms will eventually get Parkinsons disease, those patients can be appropriately treated. At the very least, these advances could greatly delay progression.

      Parkinson’s Disease and Movement Disorders Center

      Our center provides compassionate and timely treatment to patients with movement disorders, such as dystonia, ataxia, essential tremor and similar conditions. But our mission goes beyond patient care excellence. By offering educational events and support groups, we empower patients and caregivers to become better partners in their health.

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