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Tremor and slow, stiff movements are some of the most well-known symptoms of �ʲ����쾱�Բ��Dz�’s because they are the most visible. These motor system symptoms are also decisive when neurologists diagnose the condition in patients. By then, however, around half of the dopamine-producing cells in the brain will already have been destroyed. This is because Parkinson's starts several years earlier with abnormal protein clusters that appear to spread via the vagus nerve from the gut to the brain in some patients, or from the nose to the brain in others. These processes are described by Per Borghammer, consultant physician and professor of nuclear medicine at Aarhus University, in a “brain-first vs. body-first” hypothesis. 

In collaboration with his own research group and an international team of researchers, Borghammer has supported and expanded on this hypothesis with novel and decisive findings in a study just published in the scientific journal Nature Neuroscience.

The researchers analysed two large data sets from post-mortem brain tissue and demonstrated with the aid of artificial intelligence that there are not two but three variants of �ʲ����쾱�Բ��Dz�’s. 

In addition, they made a new discovery about the role played by nerve systems in the progression of �ʲ����쾱�Բ��Dz�’s. And finally, that protein also builds up in peripheral organs like the heart, gut and adrenal glands long before a diagnosis is made in body-first cases, whereas brain-first cases do not involve peripheral organs until after the time of diagnosis.

These discoveries could, for example, aid early diagnosis when cell-preserving therapy becomes available one day. 

Explosive rise in �ʲ����쾱�Բ��Dz�’s

�ʲ����쾱�Բ��Dz�’s is the fastest growing neurological condition in the world, partly because much of the global population is ageing. Around 10 million people have the condition worldwide, which is double the number from 25 years ago. In Denmark, around 12,000 people are living with �ʲ����쾱�Բ��Dz�’s, and the number is expected to increase to 20,000 by 2040.

One characteristic of �ʲ����쾱�Բ��Dz�’s, and also of Lewy body dementia, is the presence of abnormal protein clusters, called Lewy bodies, inside nerve cells. These conditions are consequently known collectively as Lewy body disease. The Lewy bodies, which are mainly made up of alpha-synuclein protein, destroy nerve cell functioning. 

Borghammer has been conducting research on �ʲ����쾱�Բ��Dz�’s for many years, with particular focus on Lewy bodies and how they spread rapidly through the body. 

He presented his brain-first vs. body-first hypothesis in 2019, and has since supported it with findings in further studies for which he received an LF Professorship in 2021. Now, Borghammer has made new discoveries about �ʲ����쾱�Բ��Dz�’s.

“For several years, I had the idea that the sympathetic nervous system plays a role in spreading Lewy bodies, because the spread in body-first patients differs so much,” explains Borghammer, commenting on the background to the latest study. 

The parasympathetic nervous system (PNS) sends signals about rest and restitution out into the body via the vagus nerve, while the sympathetic nervous system (SNS) sends “fight or flight” signals through a series of nerve nodes along each side of the spine. 

The vagus nerve is a cranial nerve that connects directly to the brain, while the SNS is linked to the brain via the spinal cord. 

“For the past five years, my aim has been to demonstrate that the SNS is just as important as the vagus nerve for how �ʲ����쾱�Բ��Dz�’s spreads in the body. We have also published several articles on this hypothesis, but have had some difficulty in calling its significance to the attention of fellow researchers,” Borghammer explains. 

He then had the idea of investigating data sets from post-mortem brain tissue and other organs for traces of Lewy bodies. 

“If we could trace patients with very early signs of the condition, and who only had those signs in the SNS, but not in the vagus nerve, that would then make a strong case for SNS involvement,” he explains. 

This aim was achieved, and more besides. 

173 Japanese brains and AI

Borghammer set about investigating the spread of abnormal protein clusters in the earliest stages of �ʲ����쾱�Բ��Dz�’s, and was consequently looking for cases with very limited protein clustering. He found this in a Japanese brain bank. The study was based on data on 173 post-mortem brain tissue specimens from Japan, 44 of which were from individuals diagnosed with �ʲ����쾱�Բ��Dz�’s before they died, but all of whom had Lewy bodies in their nervous systems.

The individual cases were placed in eight categories depending on the spread of the protein clusters, from the earliest-stage of Lewy bodies in one to two regions of the body to the most severe, and thus final-stage, showing protein clusters in 15-16 regions. They were also categorised as either brain-first or body-first.

The researchers then investigated the spread of �ʲ����쾱�Բ��Dz�’s in 16 different anatomical regions, including in the SNS and four organs outside the central nervous system (CNS): the brain, adrenal glands, oesophagus (gullet) and skin.

The studies were conducted in collaboration with researchers from Sweden, the USA, Japan and the UK, and with the aid of artificial intelligence (AI). 

The first authors of the publication, Katrine Andersen and Anushree Krishnamurthy, implemented the AI named SuStaln, which with no input other than data and by means of pattern recognition, spots where �ʲ����쾱�Բ��Dz�’s originates and spreads in the body.

�ʲ����쾱�Բ��Dz�’s outside the brain

Borghammer set about investigating the spread of abnormal protein clusters in the earliest stages of �ʲ����쾱�Բ��Dz�’s, and was consequently looking for cases with very limited protein clustering. He found this in a Japanese brain bank. The study was based on data on 173 post-mortem brain tissue specimens from Japan, 44 of which were from individuals diagnosed with �ʲ����쾱�Բ��Dz�’s before they died, but all of whom had Lewy bodies in their nervous systems.

The individual cases were placed in eight categories depending on the spread of the protein clusters, from the earliest-stage of Lewy bodies in one to two regions of the body to the most severe, and thus final-stage, showing protein clusters in 15-16 regions. They were also categorised as either brain-first or body-first.

The researchers then investigated the spread of �ʲ����쾱�Բ��Dz�’s in 16 different anatomical regions, including in the SNS and four organs outside the central nervous system (CNS): the brain, adrenal glands, oesophagus (gullet) and skin.

The studies were conducted in collaboration with researchers from Sweden, the USA, Japan and the UK, and with the aid of artificial intelligence (AI). 

The first authors of the publication, Katrine Andersen and Anushree Krishnamurthy, implemented the AI named SuStaln, which with no input other than data and by means of pattern recognition, spots where �ʲ����쾱�Բ��Dz�’s originates and spreads in the body.

Sows doubt about early diagnostics

The fact that brain-first cases showed no distinct signs of �ʲ����쾱�Բ��Dz�’s in the organs until around the time of diagnosis sows doubt about the value of recent diagnostic methods, which rely on identification of abnormal protein clusters in the gut, skin, blood and spinal fluid.

“Methods of early diagnosis have revolutionised Parkinson's care. We now have a test that makes it possible to make 90-95% accurate �ʲ����쾱�Բ��Dz�’s diagnoses based on a skin biopsy. We know that the test works for people who test positive for �ʲ����쾱�Բ��Dz�’s, and we have high expectations that this and other diagnostic methods will also be able to detect the condition 10 years earlier,” Borghammer explains. 

“But our latest research indicates that in this type of test, brain-first cases are likely to yield a negative test result because there are hardly any Lewy bodies in the peripheral organs at the time of diagnosis. Meaning that we have to go back to the drawing board to find out how we can diagnose brain-first patients in future.”

From post-mortem to clinic

Borghammer is already in full swing following up on the latest study. 

“We now have a model based on post-mortem human data. So, armed with these new insights, we’ll be returning to the clinical study and scanning patients in various ways to validate the theory of a sympathetic versus a parasympathetic sub-type.” 

The new findings about early-stage �ʲ����쾱�Բ��Dz�’s are one step on the way to a better understanding of neurodegenerative conditions involving Lewy bodies, which pose many questions yet to be answered. Professor Borghammer himself has a distinct aim in discovering the mechanisms underlying �ʲ����쾱�Բ��Dz�’s:

“The aim for the future is more individualised treatment of patients. And the more we know about variations in these medical conditions as demonstrated by these studies, the closer we will be to developing novel, personalised therapies or preventing the conditions altogether.”