User:Suhasini66/Parkinson's Disease Biomarkers



The Parkinson’s disease biomarkers are indicators of normal biological processes, pathogenic processes, or responses to interventions that are used to assess the risk or presence of disease. PD biomarkers are used to diagnose the disease in its early stage, and are intended to provide objective and reliable measures of disease progress. However, current diagnostic techniques primarily use clinical biomarkers based the presence of motor symptoms. These motor symptoms only manifest after at least 30% of nigral dopaminergic neurons have degenerated, making early diagnosis difficult. To facilitate early diagnosis, a reliable PD biomarker must be found.

Scientists are currently researching many potential PD biomarkers, ranging from clinical to biochemical indicators. Despite intensive study, none of these biomarkers have been accepted for clinical use because of various issues, most notable of which is reproducibility. With further research, these biomarkers might prove to be a reliable and help facilitate early diagnosis.

Genetic Biomarkers
Through the years, several genetic mutations have been linked to PD: a-syn (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, Leucine-rich repeat kinase 2 (LRRK2), and glucocerebrosidase (GBA). They all contribute to the onset of PD, but differ in methodology. These differences stem from the fact that each mutation disrupts different aspects of cell machinery.

SNCA is a gene that codes for alpha-synuclein, which is involved with presynaptic signaling and membrane trafficking. SNCA mutations in PD cause alpha-synuclein to aggregate into Lewey bodies. Additionally, PD patients are reported to have lower levels of alpha-synuclein as compared to controls.

The PARK2 gene encodes for the protein Parkin, which is a component of the ubiquitin-protein ligase (E3) complex. This E3 complex is part of the greater ubiquitin system that controls the targeting of proteins for degradation. PARK2 mutations cause selective degeneration of the substantia nigra and the locus coeruleus without forming Lewy bodies. More importantly, PARK2 mutations are known to causes the autosomal recessive form of PD.

The PINK1 gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction and interacts with Parkin to induce autophagy of depolarized mitochondria. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease.

The LRRK2 gene produces an enzyme called dardarin, which is largely present in the cytoplasm but also associates with the mitochondrial outer membrane. LRRK2 mutations cause the shortening and simplification of the dendrites, and have been implicated in autosomal dominant PD.

The GBA gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene are known to cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. Moreover, since 5-10% of PD patients have GBA mutations, GBA is the most prevalent and therefore significant risk factor for PD.

Biochemical Markers
Identifying biochemical biomarkers in tissues and bodily fluids is the preferred diagnostic method for many diseases, because it examines disease-associated protein levels/molecules in a relatively non-invasive way. In regards to PD, several potential biomarkers have already been identified in blood, saliva, and cerebrospinal fluid (CSF). CSF however, remains the ideal source of biomarkers because of its unique ability to quickly reflect molecular changes in the brain. Based on advances in genetic biomarker research, scientists have identified several biochemical markers such as SNCA or DJ-1 genes.

Alpha-syn was the first gene linked to PD, and its association is strongly supported by the multiple PD mutations that been identified through genome-wide association studies. Alpha-synuclein can be detected in PD patient's CSF, saliva, serum, urine, and also in the gastrointestinal tract. Research has shown that PD patients have significantly lower a-syn levels in CSF than control groups, but a-syn is not associated with disease severity. Although a-syn is the primary focus in PD research, there have been reproducibility issues because of sampling protocols, blood contamination and different operating procedures.

DJ-1 mutations also serve as biochemical markers for PD since they cause a rare form of autosomal recessive PD. DJ-1 is a protein that most notably responds to oxidative stress and is present in CSF. Research has shown that PD patients have elevated CSF levels of DJ-1 as compared to controls. However, there have been conflicting results from other studies which decreased levels of DJ-1 in a large cohort of CSF samples. This difference can again be attributed to sampling protocols, blood contamination and different operating procedures like a-syn.

In addition to a-syn and DJ-1, Apo A1 (which is a major component of high-density lipoprotein) is decreased in the plasma of PD patients as urate.

Imaging Markers
In past years, several neuroimaging techniques that indicate abnormal disease processes with higher resolution have been developed. These techniques include single photon emission tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI) and transcranial sonography (TCS). The main advantage these techniques confer is that they non-invasively track molecules significant to neurodegeneration.

Comparatively, MRI and TCS imaging are similar since they show structural changes in the brain. MRI imaging can measure hippocampal volume which research has shown to be decreased in PD. They also reveal the extent of dopaminergic neuron loss based on their ability to estimate proton density per unit area. On the other hand, TCS imaging reveals structural changes such as iron overload in the substantia nigra, a prominent risk factor for PD.

Unlike the structural measurement of MRI and TCS imaging, PET and SPECT scans assess function and monitor disease severity. PET imaging can also show a reduction in striatal dopamine, a significant PD risk factor, while SPECT imaging can estimate cerebral blood flow and dopamine transporter imaging. Both PET and SPECT imaging reveal PD dysfunction in dopaminergic neurotransmission. Despite their effectiveness, PET imaging remains unpopular because it is expensive and is only available in advanced medical centers. For this reason, SPECT imaging is more common and likely to be used in PD diagnosis.

Clinical Markers
Current diagnostic techniques focus on the manifestation of clinical symptoms, particularly motor abnormalities such as bradykinesia, rigidity, resting tremor, and postural instability. Bradykinesia refers to slowness of movement, which can appear as abnormal stillness and a decrease in facial expressivity. [7] Clinicians tests bradykinesia by having patients tap their fingers, a motion that is severely hindered (in terms of amplitude and frequency) by bradykinesia. Research has also shown that bradykinesia best correlates with nigrostriatal dopaminergic loss.

Rigidity simply refers to a PD patient’s inflexibility and decreased muscle tone. Clinicians test this by having patient’s perform a cogwheel motion and walk down a hallway. The clinicians can feel resistance/rigidity when patients perform the cogwheel motion and notice how PD patients tend not to swing their arms as frequently because of the increased rigidity. The resting tremor refers to the shaking movement that appears even when a patient’s muscles are relaxed. Although not all PD develop a resting tremor in the early stages, disease progression can be definitely observed through the exacerbation of resting tremors.

Lastly, postural instability is due to a loss of reflexes and usually only manifests in the later stages of the disease. Clinicians test for postural instability with the pull test, in which a patient is quickly pulled (by the shoulders) either backward or forward. If the patient takes more than two steps backwards or has no postural response, an abnormal postural instability can be concluded.

To evaluate the severity of motor symptoms, a number of rating scales are used. The Unified Parkinson’s Disease Rating scale (UPDRS) is the most established rating scale and evaluates behavior, mood, daily life activities (speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food), motor abilities, therapy complications, and the Hoehn and Yahr scale. The Hoehn and Yahr scale provides a general assessment of disease progression, ranging from stage 0 (no disease symptoms) to stage 5 (wheelchair bound or bedridden). [9] Research has shown that PD progression is not linear but rather variable depending on the patient. It has also shown that the deterioration rate is quicker in the early stages and in patients with the postural instability gait difficulty (PIGD) of PD.

In addition to motor symptoms, clinicians also asses several non-motor features such as REM sleep behavioral disorder, olfactory dysfunction, depression, and bowel dysfunction which often manifest before motor symptoms of PD by several years. Clinicians test these symptoms using a simple questionnaire that is non–invasive and low cost screening tests, but have limited specificity and sensitivity.

See Also:

 * Alpha-synuclein
 * Lewy body
 * Biomarker
 * Neurodegeneration