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Premotor Symptoms of Parkinson’s Disease - EHP 2013

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.

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