Neuroprotection in Parkinson's Disease: Are We Getting Close?
DIAGNOSIS OF PARKINSON'S DISEASE
Diagnosis
For neuroprotective therapies to be maximally beneficial in the treatment of PD, early diagnosis and intervention are critical. Unfortunately, early diagnosis of PD may be difficult. There is no definitive premortem diagnostic test, and standard imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans are not helpful except to exclude some other causes of neurologic dysfunction. Thus, clinical history and examination are the current standard means to diagnose PD, and clinically based diagnostic criteria have been established in the United States and United Kingdom.58,59 Additionally, other forms of parkinsonism and other neurologic disorders must be excluded. Asymmetry of motor signs and a robust and sustained response to dopaminergic medications are additional helpful diagnostic features but are not always present.
Clinical biomarkers
Motor signs of PD do not emerge until the midbrain is affected12,14 and approximately 60% of dopaminergic neurons in the substantia nigra are lost.41 Premotor symptoms, including olfactory decline, autonomic dysfunction, and rapid eye movement sleep behavior disorder, may be important biomarkers of early PD that often go unrecognized (Table 2). The identification and validation of biomarkers such as these and other premotor symptoms are critical to facilitate the early diagnosis of PD. This is currently a major research focus. For example, in the Parkinson Associated Risk Study (PARS), hyposmia (decreased olfaction) is being evaluated, along with dopamine brain imaging with 2β-carbomethoxy-3β(4-iodophenyl) tropane (β-CIT) single-photon emission computerized tomography (SPECT) in some cases, as a potential screening tool for first-degree relatives of people with PD.60
Table 2. Potential Premotor Biomarkers for Parkinson's Disease
| Strong link to PD | Weak link to PD |
|---|---|
| Olfactory dysfunction (eg, hyposmia)61,62 REM sleep behavior disorder64-66 Autonomic dysfunction (eg, constipation,69 MIBG uptake on heart scan70,71) Depression73-76 |
Excessive daytime sleepiness63 Adiposity67,68 Apathy72 Fatigue72,77 Anxiety72,76,78 RLS72 |
MIBG, metaiodobenzylguanidine; PD, Parkinson's disease; RLS, restless legs syndrome; REM, rapid eye movement.
Neuroimaging markers
Conventional imaging studies (ie, MRI and CT) are not helpful in the diagnosis of PD except to exclude other causes of neurologic dysfunction. However, functional imaging with positron emission tomography (PET), SPECT, and functional magnetic resonance imaging (fMRI) may be useful for the early detection of PD (Table 3). Functional MRI is appealing because of broad availability, lack of need for radiotracers, and favorable temporal resolution. Functional MRI has been used to evaluate changes in the brain associated with PD and to help determine the efficacy of PD therapies, and it could potentially aid in the diagnosis of early PD.79 Measurement of uptake of radiotracers using PET with dopa labeled with fluoride 18 (18F) and SPECT with 2β-carbomethoxy-3-β (4-iodophenyl) tropane (β-CIT) labeled with iodine 123 (123I) is the most commonly used method to assess presynaptic striatal dopaminergic integrity (Figure 2).80 Other radiotracers or dopamine transporter ligands can be used and may be more readily available in the future.81 These imaging assessments are considered quite reliable in identifying presynaptic dopamine deficiency states but are not widely available and do not reliably differentiate PD from other Parkinsonisms, including progressive supranuclear palsy and multiple system atrophy. Postsynaptic dopamine receptor integrity can also be assessed using PET with raclopride labeled with carbon 11 (Table 3), although this method is mainly used as an investigational tool. Recent metabolic studies with fluorodeoxyglucose (FDG) PET have identified a PD-related motor pattern (PDRP) and PD-related cognitive pattern (PDCP; Figure 3).82-84 These specific patterns of PET intensity associated with PD may be useful as neuroimaging markers for PD; however, their utility in the diagnosis of PD remains to be determined.
Table 3. Imaging Biomarkers for Parkinson's Disease
| Method | Tracer | Assessment | Expected results with PD | Limitations |
|---|---|---|---|---|
| fMRI81 | NA | Blood oxygen level as indirect marker of neuronal activity | ↓ activation in specific brain areas |
|
| SPECT81,85 | [123I]β-CIT [99mTc]TRODAT-1 [11C]MP |
Dopamine transporter levels | ↓ levels |
|
| PET81,85 | [18F]dopa | Estimate of number of dopamine terminals and nigral neurons | ↓ levels |
|
| PET81,85 | [11C]DTBZ | Binds vesicular monoamine transporter type 2 as measure of number of dopaminergic terminals and nigral neurons | ↓ levels |
|
| PET81,89 | [11C]RAC |
|
|
Influenced by age, stage of PD, and DRT |
| PET81,83,85 | FDG | Metabolic activity of basal ganglia network | ↑ PDRP and PDCP | Complex interpretation |
11C, carbon 11; 18F, fluoride 18;99mTc, technetium 99 metastable nuclear isomer; 123I, iodine 123; β-CIT, 2β-carbomethoxy-3β(4-iodophenyl) tropane; DRT, dopamine replacement therapy; DTBZ, dihydrotetrabenazine; FDG, fluorodeoxyglucose; fMRI, functional magnetic resonance imaging; MP, d-threo-methylphenidate; NA, not applicable; PD, Parkinson's disease; PDCP, PD-related cognitive pattern; PDRP, PD-related motor pattern; PET, positron emission tomography; RAC, raclopride; SPECT, single-photon emission computerized tomography.
