Premotor Parkinson's disease: Clinical features, detection, and prospects for treatment

Abstract

The period immediately before the onset of motor symptoms of Parkinson's disease (PD) often has a recognizable phenotype with features including autonomic dysfunction and impaired olfaction. Subclinical dopaminergic cell loss can also be detected at this time using molecular imaging techniques. A greater recognition of the features of premotor PD and improvements in screening technologies have opened the possibility of predictive testing for PD. In addition to molecular imaging of the dopamine system, screening tests that can potentially be used to identify the physiological abnormalities in premotor PD include olfactory testing, imaging of the sympathetic innervation of the heart, transcranial ultrasound, and genetic testing for mutations known to cause hereditary PD. All of these technologies have trade-offs as screening tests for accuracy, availability, and costs. Using these tests in combination may produce a more favorable combination of reasonable cost and accuracy than using any single test alone. Ultimately, the value of screening for PD depends on development of neuroprotective treatments for PD that would create an imperative for early identification and treatment.

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…Thus far, attempts to generate a neuroprotective therapy for PD have failed in humans, in spite of the results of promising preclinical animal studies (Siderowf and Stern, 2008;Schapira, 2009a, b). While this reflects in part the inadequacies of the available animal models, progress in this field is also significantly hindered by the lack of reliable biomarkers that would allow early (preclinical) diagnosis of the disease.…”

“…While this reflects in part the inadequacies of the available animal models, progress in this field is also significantly hindered by the lack of reliable biomarkers that would allow early (preclinical) diagnosis of the disease. Neuroprotective treatment trials are also complicated by the absence of endpoints that are biologically meaningful, and not confounded by the symptomatic effects of antiparkinsonian treatments (Schapira and Olanow, 2004;Siderowf and Stern, 2008). However, we will discuss recent evidence obtained in the Parkinson-Associated Risk Study (PARS) indicating that the combination of early nonmotor clinical markers of PD and dopaminergic imaging may provide a sensitive method to diagnose at-risk individuals before the development of motor symptoms and extensive brain degeneration.…”

Autophonic loudness perception in Parkinson's disease

“…A hypothesis of "reduced gain," or "reduced cortical motor set," whereby impaired movement preparation restricts subsequent movement extent, has been proposed to explain production difficulties (Ho et al, 1999a;Ho et al, 1999b), but this notion fails to explain the apparent inability to perceive a mismatch between heard and expected speech intensity. In fact, despite important advances in understanding parkinsonian sensory disorders in general (Tolosa et al, 2009;Siderowf and Stern, 2008), a clear hypothesis regarding the underlying mechanism of speech loudness perception deficits and its link to dysarthric motor control has yet to be developed (cf. Dagenais et al, 1999;Forrest et al, 1998;Moore, 1987).…”

When does Parkinson's disease begin?

“…Since we now accept that patients with PD frequently can present non-motor symptoms related to the PD pathological process, such as hyposmia or constipation, years before the development of classical motor signs, 7,8 in this review the term ''premotor'' phase will be used when referring to this period.…”