Developing methods for researching Premotor symptoms in PD seems so
very important. Here's an excerpt from a well-focused review.
Research on the Premotor Symptoms of Parkinson’s Disease: Clinical
and Etiological Implications
Environ Health Perspect 2013 Nov-Dec; 121(11-12): 1245–1252.
The hypothesis that premotor symptoms precede the motor signs of PD
is broadly compatible with neuropathological findings reported by
Braak et al. (2003). This work, although controversial (Burke et al.
2008), suggests that deposition of α-synuclein in the form of Lewy
bodies and Lewy neurites develops in the PD brain in six sequential
stages. α-Synuclein pathology begins in the dorsal motor nucleus of
the vagus and glossopharyngeal nerves and the anterior olfactory
nucleus in stage 1, extends to the locus ceruleus and caudal raphe
nuclei in the pons (stage 2), then to the substantia nigra (stage
3), to the temporal mesocortex (stage 4), and finally to the
neocortex (stages 5–6).
A later extension of this hypothesis further posits that the
synucleinopathy may even first develop in the enteric nerves in the
gut and later spread along the vagus nerve into the brain (Hawkes et
al. 2007, 2009). Importantly, according to the Braak hypothesis, the
irreversible loss of dopamine neurons in the substantia nigra and
associated progressive motor dysfunction may not be evident until
Braak stages 3 and 4. Although the Braak hypothesis is not
universally supported (Burke et al. 2008; Dickson et al. 2010), it
presents the intriguing possibility that the extra-nigra,
nondopaminergic pathologies are intrinsic to early PD pathogenesis
and that premotor symptoms could well be part of the disease’s
natural history (Hawkes et al. 2010).
Growing evidence on the importance of premotor symptoms, coupled
with the Braak hypothesis, has generated substantial interest in
understanding the origins and consequences of these symptoms.
Clinical research primarily has focused on evaluating premotor
symptoms and other factors as markers for the future development of
PD, a subject elegantly reviewed by Berg et al. (2012). Another
potential line of inquiry is based on the idea that the presence of
multiple premotor symptoms in the same individual represents common
underlying pathogeneses that may eventually lead to PD, and thus
premotor symptoms may provide a unique opportunity to understand the
etiology of PD (Hawkes et al. 2007, 2009). Despite this potential
promise, little research has been carried out to understand the
etiological implications of the premotor symptoms of PD.