Early and Accurate Identification of Parkinson Disease Among US Veterans
Of the prodromal features, rapid eye movement sleep behavior disorder (RBD) is associated with the highest risk of conversion to motor PD.8 Up to 80% of older men with socalled idiopathic RBD develop a parkinsonian syndrome within 20 years; risk is divided about equally between idiopathic PD and dementia with Lewy bodies (DLB).32 Collateral history from a bed-partner is usually sufficient to make the diagnosis, although, this is often confounded by the prevalence of nightmares in those with posttraumatic stress disorder in the veteran population.32 Thus, in suspected cases, obtaining a polysomnogram can aid in distinguishing between idiopathic PC and DLB.33 Given the specificity of RBD as a marker of synuclein deposition and the high risk of progression to a degenerative syndrome, accurate diagnosis and counseling is imperative.
Each of the prodromal nonmotor features of PD are at best moderately sensitive or specific in isolation, but in concert, they can be used to develop a Parkinson risk score. For instance, the MDS prodromal criteria combine individual likelihood ratios into Bayesian analysis to determine a combined probability of PD, which can be further stratified to probable or possible prodromal PD (probability > 80%, > 50%, respectively).8 These criteria have been applied to several independent cohorts and demonstrate high sensitivity and specificity, especially over time.34,35 Applicability in a veteran population has yet to be determined.
Use of Imaging in Diagnosis
Although clinical diagnostic criteria and prodromal features can improve diagnostic accuracy, it can be extremely challenging to distinguish idiopathic PD from nondegenerative parkinsonism or atypical syndromes (see below). Compared with the gold standard of pathologic assessment, the clinical diagnostic accuracy for PD ranges from 73% for nonexperts to 80% for fellowship-trained movement disorders specialists.36 Thus, objective biomarkers are sought to improve diagnostic accuracy both for clinical care as well as for research purposes, such as enrollment into clinical trials.
Multiple potential imaging biomarkers for preclinical PD can aid in early diagnosis and help differentiate PD from related but distinct disorders. While beyond the scope of this review, these techniques have recently been reviewed.7 Of these, the most widely available and accurate is dopamine transporter (DAT) imaging, which uses a radioiodinated ligand that binds to DAT on striatal dopaminergic terminals; binding is detected through single photon emission computed tomography (SPECT) scanning. Thus, a SPECT DaTscan (GE Healthcare Bio-Sciences, Little Chalfont, England) directly assesses the integrity of the presynaptic nigrostriatal system and is well correlated with severity of motor and nonmotor parkinsonism.37,38
In individuals with suspected prodromal PD, abnormal DaTscans are associated with faster progression to manifest motor PD.39 However, it should be noted that a number of medications, several of which are commonly utilized in the veteran population, can affect the outcome of a DaTscan.40 Some of these medications only mildly affect the outcome, so the physician interpreting the scan should be made aware of their use, while others need to be held for days to weeks so as not to invalidate the DaTscan. DaTscan also do not differentiate between PD and atypical degenerative parkinsonisms such as multiple system atrophy (MSA), DLB, progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS). Nevertheless, these scans can be used to distinguish degenerative parkinsonisms from other conditions that can be difficult to distinguish clinically from PD, including essential tremor, normal pressure hydrocephalus, vascular parkinsonism, or druginduced parkinsonism (DIP).
DIP usually is caused by blockade of postsynaptic dopamine receptors by antipsychotic medications, which are prescribed to as many as 1 in 4 older veterans; antiemetic agents such as metoclopramide are also potential offenders if used chronically.41 The risk of DIP appears to be associated with the D2 binding affinity of the drug. Thus, of the newer atypical antipsychotics, clozapine and quetiapine appear to have the lowest risk, while ziprasidone and aripiprazole have the highest binding affinity and therefore the highest risk.42 In many patients, parkinsonism persists even after discontinuation of the offending agent, suggesting that in at least a subset of patients, DIP may be an “unmasking” of latent PD rather than a true adverse effect of the medication. The prodromal features discussed above can be used to distinguish isolated DIP from unmasked latent PD.43 In a study we conducted in veterans at the Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, hyposmia in particular was shown to be highly predictive of an underlying dopaminergic deficit with an odds ratio of 63.44
Other important considerations in the differential diagnosis of PD are the atypical degenerative parkinsonian syndromes, formerly called Parkinson plus syndromes. These may be further divided into the synucleinopathies (MSA, DLB) or the tauopathies (PSP, CBS), depending on the predominant amyloidogenic protein. Early in the disease, the atypical syndromes and idiopathic PD may be clinically indistinguishable, although the atypical syndromes tend to progress more rapidly and often have a less robust response to levodopa.
