Biomarkers for Parkinson's Diseases

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Parkinson's disease is a brain disorder that progressively affects a person’s ability to control body movements, caused by a disorder of certain nerve cells in a part of the brain that produces dopamine, a chemical messenger the brain uses to help direct and control body movement.

Early diagnosis of Parkinson's disease gives you the best chance of a longer, healthier life. This presentation covers the information about biomarkers for Parkinson Diseases which include biological, physiological and imagine candidate / novel biomarkers.

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Biomarkers for Parkinson's Diseases

  1. 1. Biomarkers for Parkinson’s Disease Vivek Misra |B.Tech, M.S, MIANS Research Fellow The Institute of Neurological Sciences VHS Multi-Specialty Hospital & Research Institute Chennai. IN vivek@ubrf.org | @iVivekMisra http://www.ubrf.org
  2. 2. The Beginning • Search for cerebrospinal fluid (CSF) biomarkers of Parkinson’s disease (PD) began more than 25 years ago, but the most promising results are relatively recent. • In mid 80s PD biomarker research focused on reduction of dopaminergic nigrostriatal neurotransmission. • Most investigations of dopamine metabolism is based upon its major metabolite, homovanillic acid [HVA], which have been relatively uninformative. (LeWitt PA, Galloway MP. Therapy of Parkinson’s disease. 1990) Vivek Misra
  3. 3. Problem ?? Complexity underlying the pathogenesis of PD • Today, the strongest evidence for the causation of PD suggests a multifactorial intervention of genetic and environmental factors, with possible mechanisms ranging from I. dysregulated autophagy; II. protein misfolding; III. oxidative stress; IV. decreased mitochondrial energy production; V. excitotoxicity, etc (Peter LeWitta. Parkinsonism and Related Disorders. 2012) Vivek Misra
  4. 4. Need For Biomarkers • Patient usually consult a physician when characteristic motor symptom like bradykinesia, rigidity, tremor, and postural instability are significant, by then estimated 70% of the individual’s dopaminergic neurons in the brain’s nigrostriatal pathway already have been lost. • Typically, for years prior to the PD diagnosis, the patient has experienced one or more nonmotor symptoms, such as cognitive dysfunction, mood disorders, sleep problems, pain, or autonomic dysfunction. (Langston JW. Ann. Neurol 2006) • But even using the gold-standard clinical criteria for PD implemented at the best movement disorder centers, as many as 10 to 15% of individuals with other neurodegenerative diseases are misdiagnosed as having PD in the early stages of their illnesses. (Todd B. Sherer. Sci Trans Med. 2011) Vivek Misra
  5. 5. Neurobehavioral Markers • Indivisual with REM sleep behavior disorder, who are known to be at a higher risk for developing PD. Studies have found that patients with PD have a variety of sleep disturbances, including rapid eye movement behavioral disorder (RBD), that precede the onset of motor symptoms by many years or even decades. • Occulomotor Disturbance: Loss of central dopaminergic pathways involved in oculomotor control probably accounts for the impairment of saccades, observed even in early PD, but saccadic latency and amplitude have not been found to be particularly sensitive measures of disease progression. • Olfactory loss (hyposmia or anosmia) occurs in up to 90% of patients with PD and involves several impairments of odor detection, identification, and discrimination. Vivek Misra
  6. 6. Contd… • Severe dysautonomia is generally present in the advanced stages of PD, when progression of the disease and adverse effects of treatment play a role in the development of these symptoms. • Constipation tends to appear earliest, and epidemiological studies have shown that constipation can precede motor symptoms by many years. • In untreated patients with early PD, depression (37%), apathy (27%), sleep disturbances (18%), and anxiety (17%) are the most common neuropsychiatric symptoms • Another study is measuring sympathetic denervation in the heart as a risk biomarker for PD. (Wu. Y et.al Arch Neurol. 2011, Todd B. Sherer. Sci Trans Med. 2011) Vivek Misra
  7. 7. Neuro-imaging Markers Vivek Misra
  8. 8. • Functional neuroimaging modalities, including positron emission tomography (PET), single photon emission computer tomography (SPECT), and functional MRI (fMRI), provide valuable information on brain function in the neuropsychiatric aspects of PD. • Using SPECT/PET lactate/N-acetyl aspartate ratio was found to be increased in the occipital lobes in PD, particularly in PD-D patients as compared to healthy controls, suggesting that the impairment of oxidative energy metabolism is greater in PD-D. (Shi M. et.al Brain Pathol. 2011) • “7 Tesla magnetic resonance images of the substantia nigra in Parkinson's disease (Kwon DH et.al Annals of Neurology Feb 2012)” Vivek Misra
  9. 9. Dark Side of Markers • Neuroimaging techniques can detect early changes in cerebral function/atrophy, but are often I. imprecise (e.g., MRI) II. or too expensive to administer in routine clinical practice (e.g., PET). • The most commonly used outcome measure for PD clinical trials is Unified Parkinson’s Disease Ratings Scale (UPDRS), which includes both motor and nonmotor evaluations. These clinical scales are inuenced by current PD medications, can vary from day to day in individual PD patients, and are subject to both investigator and patient bias. (Todd B. Sherer. Sci Trans Med. 2011) Vivek Misra
  10. 10. Physiological Biomarkers Vivek Misra
  11. 11. Why CSF ? • CSF being much more accessible, less costly than imaging; • Reflecting metabolic and pathological states of the central nervous system; • Direct than any other body fluids when we look for CNS output; • So far the two markers that have been tested most extensively in CSF are DJ-1 and α-synuclein (α-syn), two proteins intimately involved in familial and sporadic PD pathogenesis. (Shi M. et.al. Ann Neurol. 2011) Vivek Misra
  12. 12. α- Synuclein • CSF α-synuclein concentrations as measured by ELISA are signifi cantly lower in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. (Mollenhauer B et.al. Lancet Neurol 2011) • Evidence suggests that aSYN pathology in PD may begin in the peripheral nervous system, possibly in neurons of the gastrointestinal submucosa.  In the IHC stating all PD subjects showed staining for a-synuclein in nerve fibers in colonic submucosa. No control sample showed this pattern.  Oxidative injury has been proposed as a mechanism of neuronal cell death in several neurological disorders including PD (Shannon KM et.al. Mov Dis 2011) Vivek Misra
  13. 13. • Phosphorylation of Ser-129 Is the Dominant Pathological Modification of α-Synuclein in Familial and Sporadic Lewy Body Disease. (Anderson JP et.al. J. Biol. Chem. 2006) • Approximately 90% of a-synuclein deposited in Lewy bodies is phosphorylated at Ser-129, whereas only 4% of total a-synuclein in normal brain is phosphorylated. (Foulds P et.al. Expert Rev. Mol. Diagn. March 2012) • Recent paper suggesting that the normal physiological form of the protein may be a tetramer. If found consistent, a double antibody approach to immunoassay development could actually result in a system that is able to detect these normal α-synuclein tetramers, in addition to any pathological oligomers. (Bartels T et.al. Nature 2011) Vivek Misra
  14. 14. Breakthrough with α- Synuclein • Yu Wang, et al. developed a highly sensitive and specific assay to measure PS-129 concentrations as well as total α-synuclein in CSF samples from healthy individuals and from a cohort of patients with PD, MSA, PSP, and Alzheimer's disease • Group discovered that the PS-129 concentration in CSF, when combined with the total α-synuclein concentration in CSF, helped to distinguish PD patients from those with MSA and PSP. • Additionally, CSF PS-129 concentrations in CSF correlated with disease severity in PD patients • However, before PS-129 can be deployed as a marker for PD, it will need to be validated in independent cohorts of PD patients, especially those with samples collected longitudinally. (Yu Wang, et al. Sci Transl Med March 2012) Vivek Misra
  15. 15. DJ-1 in CSF • CSF DJ-1 levels were dependent on age and influenced by the extent of blood contamination in cerebrospinal fluid and its level was decreased in Parkinson’s patients versus controls or Alzheimer’s patients when blood contamination was controlled for. (Hong Z. et.al Brain 2010) • DJ-1 and α-SYN in LRRK2 CSF do not correlate with striatal dopaminergic function. • No statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and α- SYN. • Except for a weak correlation between DJ-1 and methylphenidate binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate. (Shi M. et.al Neuro Biol Aging April 2012) Vivek Misra
  16. 16. Amyloid and tau in LRRK2 mutation carriers • Using highly sensitive and quantitative Luminex assays, researchers measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ1- 42), Flt3 ligand and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. • These biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease and multiple system atrophy. • Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from MSA, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). • “Clearly indicate that this panel of seven CSF proteins could aid in PD diagnosis, differential diagnosis, and correlation with disease severity and progression.” (Shi M. et.al Ann Neurol. 2011) Vivek Misra
  17. 17. Contd… • Aasly JO. et.al found that reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ 42 and FD uptake. • When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in cohort, significant correlations were also observed for tau. • This lead to the conclusion that the disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. (Aasly JO. et.al Neurology 2012) Vivek Misra
  18. 18. Wild Card Entries/ Novel candidate Biomarkers • The [xanthine]/[homovanillic acid] ratio also increased between the first and second CSF collections, suggesting that this quotient provides both a state and trait biomarker of Parkinson's disease. These observations add to other neurochemical evidence that links purine metabolism to Parkinson's disease. (LeWitta P. et.al BrainRes 2011) Vivek Misra
  19. 19. Contd… • Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson’s disease. Ile105 allele leads to lower activity of the enzyme, finding suggests that lower HNMT activity contributes to the pathogenesis of PD. (Palada V. et.al Neuro Biol Aging April 2012) • Sequestosome 1/p62: Neuronal cell death or proteasomal dysfunction also leads to the accumulation of misfolded and ubiquitinated proteins and causes increased expression of p62, which protects cells by localizing the misfolded proteins as aggregates in cytoplasmic inclusions. (Geetha T et.al Biomarker 2012) • Osteopontin is elevated in Parkinson’s disease and its absence leads to reduced neurodegeneration in the MPTP model. (Maetzler W. et.al J Neuro Biol Dis 2006) Vivek Misra
  20. 20. • Enzyme CoQ10: Discovery of multiple PD genes whose function is linked to mitochondrial function or oxidative stress, although not proof, strongly supports a role for mitochondrial involvement in PD-associated neurodegeneration, where enzyme CoQ10 plays a important role. (Spindler et al. Neuropsych Dis Treat 2009) • Multiple analyses resulted in four significant genes: proteasome (prosome, macropain) subunit-a type-2 (PSMA2), laminin, b-2 (laminin S) (LAMB2), aldehyde dehydrogenase 1 family-member A1 (ALDH1A1), and histone cluster-1 H3e (HIST1H3E) differentiating between medicated PD subjects versus controls. (Gerlach M et.al J Neural Transm March 2012) Vivek Misra
  21. 21. Contd… Peripheral markers in neurodegenerative patients and their first-degree relatives (Cristalli DO et.al J Neuro Sc March 2012) • NOx, (thiobarbituric-acid reactive substances) TBARS and PCs (protein carbonyls) in erythrocytes, and NOx and TBARS in leukocytes are potential biomarker for PD patients. • The pattern of changes observed with Parkinson's disease patients was clearly different from that of the AD group. • Relatives of Parkinson patients showed elevated levels of NOx in leukocytes. Vivek Misra
  22. 22. Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics (Gerlach M et.al J Neural Transm March 2012) Vivek Misra
  23. 23. Vivek Misra
  24. 24. Unbiased “omics” discovery: For Biomarker Identification • A transcriptome-wide scan using RNA microarrays in whole blood of patients with early-stage PD identified a molecular multigene marker that is associated with risk of PD. • Microarray: Genomic technologies such as microarray enable the simultaneous interrogation of the expression level of thousands of genes to obtain a quantitative assessment of their differential activity in a given tissue or cell. This suggests that gene/RNA expression signals that can be measured in routinely collected blood samples could facilitate the development of biomarkers for PD. • Metabolomics: Using metabolomic technologies, several recent preliminary studies have identified metabolomic signatures in plasma/serum and urine in PD which appear to separate PD patients from controls. Vivek Misra
  25. 25. • Proteomics: Proteomics is the study of both the structure and function of proteins by a variety of methods. The emerging technology of quantitative proteomics also provides a unique opportunity to reveal static or perturbation-induced changes in a protein profile. • Indeed, compared to genomics and metabolomics, proteomics perhaps has garnered more recent attention, largely because proteins are readily available in body fluids (a particularly important point in diseases of the CNS) and are more stable than mRNA and metabolites. (Caudle WM et.al Expert Rev Neurother. 2010) Vivek Misra
  26. 26. The Parkinson’s Progression Markers Initiative (PPMI) Vivek Misra
  27. 27. Key advances 2011 Christine Klein and Dimitri Krainc. Nat. Rev. Neurol. 8, 65–66 (2012) • α-Synuclein and glucocerebrosidase form a bidirectional pathogenic loop, providing an important pathophysiological mechanism in the development of Parkinson disease. • Next-generation sequencing has led to the discovery of a new gene (VPS35) associated with late-onset PD; this finding implicates retrograde transport in PD pathogenesis. • α-Synuclein-reactive antibodies may serve as a new biomarker for PD, especially in its early phase iPSCs -derived neurons represent a patient-specific cellular model with great potential for the study of disease biology. • The first double-blind, sham-surgery controlled, randomized trial of viral gene transfer of glutamic acid decarboxylase resulted in improved motor scores in patients with PD, and the treatment was not associated with severe adverse events Vivek Misra
  28. 28. Thank You Vivek Misra
  29. 29. References. • Kwon DH. Et.al. 7 Tesla magnetic resonance images of the substantia nigra in Parkinson's disease. Annals of Neurology. Volume 71, Issue 2, pages 267–277, February 2012 • Mollenhauer B, et.al. α-Synuclein and tau concentrations in cerebrospinal fl uid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 2011; 10: 230–40 • Shannon KM et.al. Alpha-Synuclein in Colonic Submucosa in Early Untreated Parkinson’s Disease. Movement Disorders May2011. • Gerlach M et.al Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics. J Neural Transm (2012) 119:39–52 • Shi M et.al Biomarkers for Cognitive Impairment in Parkinson Disease. Brain Pathol. 2010 May • Todd B. Sherer. Biomarkers for Parkinson’s Disease. SciTranslMed 2011 Vivek Misra
  30. 30. • J.O. Aasly et al. Cerebrospinal fluid amyloid b and tau in LRRK2 mutation carriers. Neurology 2012 • Spindler et.al Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatric Disease and Treatment 2009:5 597–610 • Shi M. et.al Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression. Ann Neurol. 2011 March • LeWitta P. CSF xanthine, homovanillic acid, and their ratio as biomarkers of Parkinson's disease. Brain Research 2011 • Hong Z et.al DJ-1 and a-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain Research 2010 • Shi M. et al. DJ-1 and SYN in LRRK2 CSF do not correlate with striatal dopaminergic function. Neurobiology of Aging 33 (2012) • Bogaerts V et.al Genetic findings in Parkinson’s disease and translation into treatment: a leading role for mitochondria? Genes, Brain and Behavior (2008) 7: 129–151 Vivek Misra
  31. 31. • Palada V. et al. Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson’s disease. Neurobiology of Aging 33 (2012) • Maetzler W. et.al Osteopontin is elevated in Parkinson’s disease and its absence leads to reduced neurodegeneration in the MPTP model. Neurobiology of Disease 25 (2007) • Caudle MW et.al. Using ‘omics’ to define pathogenesis and biomarkers of Parkinson’s disease. Expert Rev Neurother. 2010 June • Foulds P et.al Phosphorylated a-synuclein as a potential biomarker for Parkinson’s disease and related disorders. Expert Rev. Mol. Diagn. 12(2), 115–117 (2012) • Yu Wang, et al. Phosphorylated a-Synuclein in Parkinson's Disease. Sci Transl Med 4, 121ra20 (2012) • Wu Y. et.al. Preclinical Biomarkers of Parkinson Disease. Arch Neurol. 2011;68(1):22-30 Vivek Misra
  32. 32. • LeWitt P. Recent advances in CSF biomarkers for Parkinson’s disease. Parkinsonism and Related Disorders 18S1 (2012) S49–S51 • Geetha T et.al. Sequestosome 1/p62: across diseases. Biomarkers, 2012; 17(2): 99–103 Vivek Misra

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