Disease may start in its autonomic nerve endings and ascend to the brainstem.
Results of imaging studies provide important clues about where Parkinson’s disease (PD) originates in the nervous system, according to Per Borghammer, MD, PhD, DMSc.
Borghammer, a senior consultant and associate professor in the Department of Nuclear Medicine & Positron Emission Tomography (PET) Centre, Aarhus University Hospital in Denmark, recently explained why imaging the pathology of neurodegenerative movement disorders like PD is both important and difficult at the 21st International Congress of Parkinson’s Disease and Movement Disorders in Vancouver, BC.
He began with findings from imaging studies of defective versions of the neural proteins synuclein and tau. To Borghammer, the most important goal in neuroimaging is to develop a synuclein PET tracer, like those already developed for amyloid and tau. Because α-synuclein may help regulate the release of dopamine — which is critical for controlling movement — imaging defective versions of α-synuclein could provide a better understanding of PD.
With a synuclein PET tracer, researchers could better image and stage PD pathology and determine whether it begins in the peripheral nervous system, Borghammer said. And because α-synuclein inclusions appear before neurodegeneration, detecting them could predict PD before motor symptoms appear.
With such a tracer, researchers could use a positive PET scan as an inclusion criterion in clinical trials and better evaluate PD treatment response.
However, developing this PET tracer has been challenging because pathological synuclein appears in multiple forms in many different structures modified in many ways, Borghammer said. And because synuclein aggregates are mainly intracellular, its PET tracer must cross both the cell membrane and the blood brain barrier.
Synuclein aggregates contain many other proteins but are not as common as those proteins, so PET ligands for synuclein must have very high selectivity for it. As a result, no good PET tracer for synuclein is available, Borghammer said.
Tau imaging has been “a bit more encouraging,” he noted. An explosion of tau papers in 2016 is still expanding, with imaging researchers uncovering that the brains of late-stage PD patients contain a lot of tau, which may cause PD dementia.
In contrast, cognitively intact PD patients had no significant increase in tau. A few with mild cognitive impairment or PD dementia had slightly elevated levels.
“So the conclusion is there is no significant tau in non-demented PD patients,” Borghammer said.
He also covered the use of dopaminergic tracers to image neurodegeneration. Neuroimagers have used these tracers extensively to image dopaminergic terminals but less frequently to study cell bodies. Findings have been “in line with what most of us know or believe — that PD is mostly a disease of the nerve terminals."
"So there’s more damage in the terminals and less in the cell bodies,” Borghammer said.
He added that because the nerve cell bodies are still alive, they might be able to regrow their terminals, and neuroimagers can examine that regrowth further now with AV-1451, a tau tracer that also binds very selectively to neuromelanin. This dark, dopamine-based pigment related to melanin occurs in large quantities in catecholaminergic cells of the locus coeruleus (LC), which influences balance, posture, behavioral inhibition, and sleep, and of the substantia nigra, important in movement.
Imaging studies indicated that on average, PD patients had a 30% loss in neuromelanin and a 50% loss of it in dopaminergic nerve terminals in the nigra.
Investigators also used magnetic resonance imaging (MRI) to view neuromelanin in the LC, Borghammer said, and found a decrease with PD patients with rapid eye movement (REM) behavior disorder (RBD), but none in those without RBD — indicating that the LC contributes to RBD.
Researchers have also imaged the noradrenergic system with PET scans by using a carbon-11- containing ligand that binds to the norepinephrine transporter, he added. One such study found a decreased tracer signal in the pallidus in PD patients compared with controls.
However, only PD patients with RBD had a significant decrease in this signal in the LC.
“So I think this tracer has the potential to investigate non-motor symptoms [like sleep disturbance] and how they correlate with this measure of the noradrenergic system,” Borghammer said.
In up to 90% of patients early in the disease, PD affects the vagus nerve, which innervates the internal organs via the parasympathetic nervous system, Borghammer said. As a result, he has been imaging the nerve terminals of the digestive organs by using carbon-11 donepezil PET, which has resulted in a nice, strong signal in healthy subjects but a pale, weak signal reflecting disruption in PD patients. Because donepezil (Aricept/Pfizer) binds to acetylcholinesterase (ACHE), a weak donepezil signal indicates a decrease in ACHE in catecholaminergic neurons from disrupted transport of ACH.
Donepezil imaging studies by Borghammer and others showed how PD progresses in these organs.
“At diagnosis, the pancreas is normal," Borghammer said. "But some years later, you start to see a decreased signal. The small intestine is already showing a decrease, and that progresses after 4 years. And the most extreme signal deficit is seen in the colon."
Borghammer is also doing imaging to test the peripheral or dual-hit hypothesis that, in some cases, PD pathology starts in the autonomic nerve endings of the gut and travels from there via the sympathetic nervous system to the brainstem.
“I find this to be very interesting stuff,” Borghammer said commented.
He is testing this hypothesis in RBD patients, who he believes should be in Braak stage 2 because the LC is heavily involved. However, if the pathology starts in the peripheral nervous system and travels up to the brainstem, the periphery may be even more affected than the core, Borghammer said.
Borghammer is also using several types of imaging to do in vivo functional Braak staging in 20 RBD patients carefully selected to have no comorbidities that would interfere with measurements. Unpublished preliminary results showed that the pathology in PD follows an ascending path, "like a forest fire."
“This data is certainly compatible with the peripheral hypothesis, [although] it doesn’t prove it,” Borghammer said.
Finally, Borghammer addressed the functional deficits in PD, particularly those that result in constipation, an important PD symptom that may be prodromal. When it is assessed subjectively, 40% to 50% have constipation.
"But if you are interested in the underlying pathology, you should measure it objectively because then you would find that perhaps 65% to 80% have colonic dysfunction,” Borghammer said.