**5. Parkinson's disease and olfactory impairment**

A major factor leading to neurodegenerative PD pathology is the loss of dopaminergic neurons from the substantia nigra, resulting in slow but substantial loss of dopamine that eventually leads to many clinical motor symptoms such as bradykinesia, rigidity, tremor, instability of posture and decline of cognitive function [66]. The olfactory system is a severely affected non-motor system in PD patients with early appearance of olfactory dysfunction that remains independent of progressive PD symptoms, their duration and treatment [67]. Additional research studies have indicated association of olfactory dysfunction with PD for over three decades [25, 68]. Olfactory dysfunction, including hyposmia and decline in olfactory acuity, has been established as one of the earliest features of PD. These are detectable in approximately 90% of early stage PD patients, where they may precede the onset of the motor symptoms by a margin of years [69–73]. Hyposmia and progressive olfactory decline in PD patients have been attributed to central olfactory processing, since the olfactory epithelium biopsy samples of PD patients were normal [74]. Subsequent MRI studies indicate a varying degree of reduction in olfactory bulb volume and depth of olfactory sulcus in PD patients than in normal control individuals. These studies indicate an association of anatomical changes with altered olfaction in PD patients [75]. Lewy bodies and Lewy neurites comprised of α-synuclein are histological hallmarks of neurodegenerative pathology in PD [76]. The olfactory bulb and lower brainstem have been considered as the induction site for the onset of histopathological features comprising of both Lew bodies and Lewy neurites [73, 77]. Along with the peripheral nervous system, such histological aberrations also begin to appear in gut nerve plexa and the olfactory bulb, thereby indicating participation of olfactory bulb cell layers in the progression of neurodegenerative pathology of PD [78].

Dementia associated with PD, known as Parkinson's disease dementia (PDD), is one of the most debilitating symptoms of PD and is difficult to predict during early stages of the disease. A research study using OSIT-J (odor stick identification test for Japanese) shows over 18 fold increase in risk of dementia for PD patients with severe hyposmia [79]. Indeed OI has emerged as a reliable tool for providing excellent diagnostic accuracy for PD distinguishing it from PD mimics [80].
