Ap­pendix may play role in Parkin­son’s

Study finds those who have had the or­gan re­moved are less likely to get dis­or­der.

Los Angeles Times - - CALIFORNIA - MELISSA HEALY melissa.healy@la­times.com

Sci­en­tists have found that peo­ple who had the or­gan re­moved were 20% less likely to de­velop the dis­or­der.

The ap­pendix has long been dis­missed as an or­gan that has out­lived its use­ful­ness in hu­man evo­lu­tion. But new re­search sug­gests it may play an ac­tive — and detri­men­tal — role in the devel­op­ment of Parkin­son’s dis­ease.

In a find­ing that ex­tends the link be­tween gut and brain health in a sur­pris­ing new di­rec­tion, sci­en­tists found that peo­ple who had their ap­pendix re­moved were 20% less likely to de­velop the neu­rode­gen­er­a­tive dis­or­der than peo­ple who did not have ap­pen­dec­tomies.

What’s more, sur­gi­cal re­moval of the ap­pendix seemed to fore­stall the ap­pear­ance of Parkin­son’s symp­toms, which in­clude tremors, move­ment dif­fi­cul­ties and signs of de­men­tia. Among older pa­tients in whom Parkin­son’s dis­ease was even­tu­ally di­ag­nosed, those who’d had their ap­pendix re­moved ex­pe­ri­enced their first symp­toms 3.6 years later, on aver­age, than peo­ple who re­tained the tiny or­gan.

The au­thors of the new study, pub­lished last week in the jour­nal Sci­ence Trans­la­tional Medicine, stressed that their find­ings do not make the case for ap­pen­dec­tomies as a strat­egy to pre­vent Parkin­son’s.

Rather, they said, the study of­fers new ev­i­dence for an idea that is gath­er­ing sup­port among sci­en­tists ex­plor­ing the ori­gins of Parkin­son’s dis­ease: that at least in some cases, the pro­teins that ac­cu­mu­late in the brain and shut down pro­duc­tion of dopamine are hatched in the gas­troin­testi­nal tract, pos­si­bly by the im­mune sys­tem.

From there, sci­en­tists sus­pect that those pro­teins — called al­pha-synu­clein — mi­grate north along the va­gus nerve, one of the long­est nerves in the body. In Parkin­son’s, th­ese pro­teins some­how get “mis­folded” and con­trib­ute to the for­ma­tion of clumps called Lewy bod­ies, which in­vade and dam­age a site in the brain that helps reg­u­late move­ment.

Al­though far from de­fin­i­tive, this emerg­ing pic­ture of Parkin­son’s dis­ease has be­gun to fo­cus sci­en­tists on ways they might de­tect and even treat it years be­fore it harms the brain. Gas­troin­testi­nal symp­toms such as chronic con­sti­pa­tion are of­ten ev­i­dent in peo­ple years be­fore they are di­ag­nosed with Parkin­son’s — a fact that has fos­tered in­ter­est in the brain-gut con­nec­tion in the dis­ease, and in the pos­si­bil­i­ties of ear­lier de­tec­tion .

But there are still many mys­ter­ies to un­ravel. Sci­en­tists must nail down the full cast of char­ac­ters — in­clud­ing genes, en­vi­ron­men­tal tox­ins and mis­folded pro­teins — im­pli­cated in the ini­ti­a­tion and pro­gres­sion of the dis­ease. They must dis­cern where and how the dis­ease process be­gins. And they must un­der­stand the ex­act se­quence of events by which th­ese mul­ti­ple con­trib­u­tors in­ter­act to do dam­age.

The new find­ings sug­gest that the ap­pendix should be a spe­cial place of in­ter­est in this hunt.

“It’s a piece to the puz­zle,” said Dr. Rachel Dol­hun, a neu­rol­o­gist and vice pres­i­dent for med­i­cal com­mu­ni­ca­tions at the Michael J. Fox Foun­da­tion, a ma­jor fun­der of Parkin­son’s dis­ease re­search. “It sug­gests pro­tein mis­fold­ing that might hap­pen in pe­riph­eral or­gans to be an ini­ti­at­ing fac­tor in the dis­ease, and that the ap­pendix might be an or­gan that could con­trib­ute.”

Sci­en­tists first ob­served two decades ago that ab­nor­mal al­pha-synu­clein pro­teins were ev­i­dent in the brains of peo­ple with Parkin­son’s dis­ease, as a com­po­nent of Lewy bod­ies. More re­cently, they have dis­cov­ered that, in their nor­mal form, th­ese al­phasynu­clein pro­teins were wide­spread in the guts of healthy younger peo­ple.

Sus­pi­cions have in­creas­ingly fallen upon the ap­pendix as a nurs­ing ground for the po­ten­tially trou­ble­some pro­teins. A thum­b­like pro­tu­ber­ance from the large in­tes­tine, the ap­pendix is a com­mon site of acute in­flam­ma­tion, caus­ing pain and in­flam­ma­tion through­out the gut. Sur­geons rou­tinely re­move it when it flares.

But as sci­en­tists have stud­ied the di­ges­tive tract’s di­verse ecosys­tem of mi­crobes, they have gained an in­creas­ing ap­pre­ci­a­tion for the role of the ap­pendix in reg­u­lat­ing im­mune re­sponses in the gut — with reper­cus­sions through­out the body. If al­pha-synu­clein is cre­ated there, or if the ap­pendix spawns the mis­folded pro­teins that are the hall­mark of Parkin­son’s dis­ease, the pres­ence or ab­sence of an ap­pendix should make a dif­fer­ence in a per­son’s like­li­hood of de­vel­op­ing that dis­ease, the au­thors of the new study rea­soned.

It was a hy­poth­e­sis they could test, if they were able to scour the com­pre­hen­sive med­i­cal records of a huge pop­u­la­tion over many decades. In Swe­den, a coun­try with metic­u­lous record­keep­ing and a na­tional registry of pa­tients fol­lowed from cra­dle to grave, they had two op­tions.

One was a database that con­tained de­tailed med­i­cal records for 1.6 mil­lion Swedes over an aver­age of 54 years. Many of them had ap­pen­dec­tomies; far fewer of them were di­ag­nosed with Parkin­son’s.

The anal­y­sis re­vealed that re­mov­ing the ap­pendix early in life was as­so­ci­ated with a roughly 20% re­duced risk of de­vel­op­ing Parkin­son's dis­ease.

The ef­fect was mag­ni­fied in peo­ple who lived in ru­ral areas. En­vi­ron­men­tal con­tam­i­nants have been found to drive up Parkin­son’s risk, and greater ex­po­sure to pes­ti­cides in ru­ral areas is widely thought to ex­plain the greater preva­lence of the dis­ease there. In that pop­u­la­tion, ap­pen­dec­tomies were as­so­ci­ated with a 25% lower risk of Parkin­son’s. When the re­searchers con­sid­ered the tim­ing of an ap­pen­dec­tomy, they found fur­ther ev­i­dence to sug­gest a cen­tral role for the ap­pendix in Parkin­son’s dis­ease.

The de­cline in Parkin­son’s risk was ap­par­ent only when the ap­pendix (and the al­pha-synu­clein pro­teins con­tained within it) were re­moved early in life. Re­moval of the ap­pendix af­ter the dis­ease process starts, how­ever, had no ef­fect on dis­ease pro­gres­sion, they found.

The study au­thors also an­a­lyzed ap­pendix tis­sue sam­ples ob­tained from 48 peo­ple who had un­der­gone rou­tine ap­pen­dec­tomies and were not di­ag­nosed with Parkin­son’s later in life. They found that 46 of the sam­ples con­tained high lev­els of al­pha-synu­clein clumps sim­i­lar to those seen in Lewy bod­ies, and that the age of the per­son from whom they were ex­cised did not seem to mat­ter. In a dis­ease linked to ad­vanced age, this was a sur­prise.

In the lab, the re­searchers found that this ex­cised tis­sue from healthy in­di­vid­u­als could eas­ily be made to form the dan­ger­ous clumps seen in the brains of peo­ple with Parkin­son’s.

All of this sug­gests a model in which rogue species of al­pha-synu­clein might jump-start the for­ma­tion of mis­folded pro­tein clumps in­side the ap­pendix, the au­thors wrote.

But that doesn’t mean the rid­dle of Parkin­son’s dis­ease, first de­scribed in 1817 by Dr. James Parkin­son, is close to be­ing solved. (Co­in­ci­den­tally, Parkin­son was the first to de­scribe acute ap­pen­dici­tis, in 1812.)

“There could be many ori­gins” of the dis­ease, said coau­thor Vi­viane Labrie, a neu­ro­ge­neti­cist at the Van An­del Re­search In­sti­tute in Grand Rapids, Mich. The re­moval of the ap­pendix “seems to be as­so­ci­ated with a 20% re­duc­tion in that risk.” But while that is a ro­bust find­ing, she said, it leaves much to be ex­plained.

“This work is nicely done, and there is a lot of power in the size of the pop­u­la­tion th­ese au­thors used,” said Anu­man­tha Kan­thasamy, a Parkin­son’s re­searcher at Iowa State Univer­sity in Ames who was not in­volved in the new re­search.

Kan­thasamy stressed that the as­so­ci­a­tion found in the study does not nec­es­sar­ily sug­gest that re­moval of the ap­pendix di­rectly low­ered Swedes’ risk of Parkin­son’s. The re­la­tion­ship could well be more com­plex: For in­stance, the ap­pen­dici­tis at­tack that led to the or­gan’s re­moval might ul­ti­mately be found to be the key to a per­son’s pro­tec­tion.

“It adds to the con­cept that, in Parkin­son’s dis­ease, changes that take place in the pe­riph­eral ner­vous sys­tem, in­clud­ing the gut, prob­a­bly oc­cur much ear­lier than what you see as the clas­si­cal pathol­ogy in the brain,” he added. “And it adds to our un­der­stand­ing that the gut and the pe­riph­eral ner­vous sys­tem are in­ti­mately con­nected to the brain.”

B.A. Killinger et al. Sci­ence Trans­la­tional Medicine

HEALTHY APPENDIXES con­tain al­pha-synu­clein (shown in red), a pro­tein that is a con­stituent of the Lewy bod­ies ob­served in Parkin­son’s dis­ease.

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