Improving Outcomes Through Early Diagnosis of Parkinson’s Disease | Page 2

If early intervention to slow or halt disease progression in PD is to be achieved, it is necessary that the skills and resources for early detection of the disease become more refined and widely disseminated. This means that misdiagnosis of PD must become less common and that knowledge of the means of early detection of PD must become more widespread. At present, no single diagnostic test is available for PD, and accurate diagnosis—early or otherwise—has been a significant challenge, particularly among clinicians without particular expertise in movement disorders. The subjective nature of PD diagnosis, which relies on a group of physical and neurological assessments—none of which are, in themselves, diagnostically conclusive—has been an obstacle to accurate diagnosis. Nevertheless, the situation for PD diagnosis is improving and, recently, a number of new and diverse techniques for diagnosis, including early PD diagnosis, have been emerging and have the potential to considerably alter the diagnostic landscape.

Premotor Symptoms

Despite the reliance on motor symptoms for the standard diagnosis of PD, premotor symptoms hold promise for the early diagnosis of PD, and considerable progress has been made in recent years in establishing premotor symptoms as a means of identifying PD much earlier than in the past. One important observation—and one that may require rethinking certain assumptions about the fundamental nature of PD—is that PD is not simply a central nervous system (CNS) disease in which the peripheral nervous system (PNS) plays a minor part. Rather, there appears to exist a much larger role for the PNS than previously assumed, particularly in the early stages of the disease. Many of the premotor symptoms that arise in early PD emerge in PNS structures, such as the sympathetic cardiac plexus and vesicoprostatic plexus, and there is compelling evidence to suggest that PD actually begins in the PNS.^22,23

The manifestations of premotor symptoms in PD are diverse, affecting olfactory structures, gastrointestinal and urinary function, and mood and sleep, as well as a variety of cognitive and autonomic functions. Gastrointestinal dysfunctions that manifest as premotor symptoms include gastroparesis and constipation. Urinary frequency, urgency, and nocturia constitute primary urinary dysfunctions in early PD. Sexual dysfunction in both men (erectile and ejaculation dysfunction) and women (poor vaginal lubrication and difficulty achieving orgasm) have also been observed as PD premotor symptoms. Mood disorders, including depression and anxiety, are well documented in the premotor phase, while sleep disturbances, including REM behavior disorder and excessive daytime sleepiness, are common premotor symptoms. Other nonmotor PD symptoms that may play a role in the premotor phase include pain, apathy, restless legs syndrome, fatigue, and poor ability to discriminate colors.²³

Hyposmia, a well-known feature of PD,²⁴ may be the most notable of nonmotor symptoms observed in the premotor stage, in part because of the growing quantity of data demonstrating and explicating the role of olfactory loss in PD, but also because it may represent a highly useful means of achieving diagnosis of PD much earlier than has been possible up until the present. Indeed, a number of studies have sought, and are seeking, to determine its utility in PD diagnosis, with promising, if not yet fully utilizable, results. However, it should be noted that hyposmia is also associated with other conditions, including Alzheimer’s disease and dementia with Lewy bodies, and thus the presence of hyposmia may be useful for the identification of persons at risk for PD, rather than being diagnostic of PD.²⁵

One early study of olfactory function in parkinsonism (published in 1995), conducted by Wenning et al, employed the 40-odorant forced-choice University of Pennsylvania Smell Identification Test (UPSIT) to examine olfactory patterns in patients with idiopathic PD as well as several other parkinsonian syndromes, while also evaluating the utility of the UPSIT itself in this context. The patient population included 118 subjects with PD, 29 with MSA, 15 with PSP, and 7 with CBD.²⁶ The investigators found that compared with PSP, CBD, and MSA patients, PD patients scored significantly lower on the UPSIT. The UPSIT demonstrated a sensitivity of 77% and specificity of 85% in distinguishing PD from the atypical parkinsonian syndromes.²⁶ These results are certainly encouraging, if not conclusive, in positioning olfactory testing as a means of early PD detection.

A study from the United Kingdom recruited 18 PD patients, 14 patients with vascular parkinsonism (VP), and 27 matched controls, and compared their olfactory function using UPSIT.²⁷ The authors found a highly significant difference in UPSIT scores between PD and VP patients, and also between PD patients and controls (both P <.0001). There was no significant difference between the VP patients and controls. The authors found that the overall sensitivity of UPSIT was 86% and the specificity 89%. However, when the study subjects were divided into 2 age groups (65-75 and 76-88 years), UPSIT sensitivity and specificity in the younger group was 100% and 86%, respectively, compared with 86% and 80%, respectively, in the older group.²⁷ It is conceivable that these results may have additional implications for early detection (if the younger group might be presumed to have, on average, less advanced disease), although these age-difference results may simply reflect the deterioration of olfactory function with advancing age.

A separate UK study employed UPSIT to compare 18 subjects with PD to 17 subjects with early-onset parkinsonism (EOPD) who possessed the PARK2 mutation (parkin-positive), 11 EOPD patients without PARK2 (parkin-negative), and 28 matched controls.28 Highly significant differences in reduced scores were observed between the PD group and both the parkin-positive and health control groups (both P <.0001). The PD group scores were also significantly lower than the parkin-negative group, although the overall difference was less robust (P = .046).²⁸