PD Paradigm shift: Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis.

[aspergerian13]

An important hypothesis about PD origins was recently published. The abstract conveys the rationale.(open access).

IMO, researchers Per Borghammer and Nathalie Van Den Berge may have clarified and connected the diverse findings in PD and related alpha synuclein pathologies.

I have long realized that the locus coeruleus is a major factor in my PD. My prodrome included sleep problems, leg cramps, and constipation. I am a gut first person. Also, I have documented autonomic issues.

A recent thread by Blackfeather addresses gut first or brain first.

healthunlocked.com/parkinso...

Which of the two major subgroups explained in the essay fits you?

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis.

IOS Press. Open access.

content.iospress.com/articl...

Abstract

Parkinson’s disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence— reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.

J Parkinsons Dis, 9 (s2), S281-S295.

Authors: Per Borghammer 1 2, Nathalie Van Den Berge 2.

Affiliations:

1Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark.

2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

PMID: 31498132.

****.

See also:

PMC ANS: The Parkinson's progression markers initiative (PPMI) – establishing a PD biomarker cohort.

ncbi.nlm.nih.gov/pmc/articl...

****.

Search HU PD for Autonomic and for Coeruleus.

[aspergerian13]

Also:

What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies | Journal of Neurology, Neurosurgery & Psychiatry. jnnp.bmj.com/content/87/3/319

[jimcaster]

This is purely anecdotal, but I'm reminded of my post several months ago asking whether people's first symptom was and what their current most notable symptom is. For many people, constipation was their first symptom and now they are tremor dominant. For others (like me), loss of sense of smell was their first symptom and they are not tremor dominant. I wonder if the first group's PD originated in the gut, while my cohorts and my PD originated in the brain and/or olfactory bulb.

[aspergerian in reply to jimcaster]

Jimcaster,

You set forth important nuances.

[1rocketman in reply to jimcaster]

My husband always claimed to have a poor sense of smell, which he attributed to all the smoke and chemicals he inhaled as a firefighter. He also has no tremors, though I notice an occasional flicker of his thumb.

Early in our relation back in 1997, I noticed he walked oddly, but I couldn't put my finger on it. In retrospect, I realize now that he didn't have a natural swing in his arms.

Currently, his major complaint is stiffness on his off time-- around 3.5 hours after last taking his C/L and B1.

[LAJ12345 in reply to jimcaster]

I remember we discussed this a while back and did a survey and it was mostly true I think. Did you have hay fever as a kid? I wondered if the nose one went with allergies. Although I’m sure my husband had gut problems too and gluten sensitivity, but has the smell and non tremor type.

[jimcaster in reply to LAJ12345]

I did have allergies, but nothing too severe.

[Hidden in reply to jimcaster]

Sorry to burst your bubble but I am tremor dominant and Iost sense of smell first.

[aspergerian13 in reply to Hidden]

The newly published hypothesis will probably bring forth numerous anecdotes that are exceptions to what Borghammer and Van den Berge presented. Indeed, there are likely to be many PwP etc who have pathologies active in both domains.

[aspergerian13 in reply to aspergerian13]

I too had impaired olfaction, documented by researchers at University of Iowa, 2006.

My PD was diagnosed in 2011, months after a lacunar infarct had occurred. (August 2010).

My type:

Pure motor stroke/hemiparesis (most common lacunar syndrome: 33–50%).

en.m.wikipedia.org/wiki/Lac...

[jimcaster in reply to Hidden]

I remember that there were some exceptions, but I was struck by the constipation-tremor and loss of smell-rigidity relationships. It's purely anecdotal at this point, but I wish it could be studied further. I believe Parkinson's disease is not a single disease and that a cure for some of us may not work for all of us, but who knows?

[weekapaw in reply to jimcaster]

Around 10 years ago, I had ruptured Diverticulitis (like appendicitis but in Large intestine) Resulting in removal of a foot of colon, and wearing a bag for 3 months. Within a year I started getting joint pains everywhere. I went to various doctors who found nothing. Shortly after, I started having terrible itching on hands and feet best described as Nephropathy but with itching. Some time later I developed a hand tremor and started falling down. I was given a DATScan (5 years ago, and here we are.

I truly believe MY PD Came from my gut.

I should mention that I have the LRRK2 gene which has given me ADD/ADHD, Tourettes, and RLS, all linked to the gene.

In my humble opinion, there must be multiple causes for PD. I think Genetic PD may be a different syndrome than not genetic.

What is also interesting (to me) is at birth, my neck was nicked by the forceps (I'm 71) resulting in an infection and given Antibiotic, which may have screwed up my Flora resulting in ADD Etc.??

[aspergerian13 in reply to weekapaw]

Your anecdotal summary is important. See:

PMC: Triggers, Facilitators and Aggravators: Redefining Parkinson’s Disease Pathogenesis.

2019.

ncbi.nlm.nih.gov/pmc/articl...

[chartist in reply to jimcaster]

Jim,

One of my friends with PD is tremor dominant, never had an issue with constipation and has loss of smell. PD seems to have many variables!

Art

[aspergerian]

Autonomic dysfunction presenting as orthostatic intolerance in patients suffering from mitochondrial cytopathy. - 2010.

ncbi.nlm.nih.gov/pubmed/209...

[Zella23]

My husband started symptoms - frozen shoulder, lack of arm swing, shoulder stiffness, loss of sense of smell and slow movement! Gradually happening 3 months after blood pressure meds! I always suspect a link to those!

Not diagnosed for 4 years after that although symptoms were there! No constipation or problems with sleep! I suspect it wasn’t gut related. He had asthma and hay fever as a child but not so much now. Has tremor but not tremor dominant. Responds to C/L and B1 and other supplements.

[aspergerian13]

20 years of gradual development of pathology with symptoms:

In 2003, it was hypothesized that initial pathological alpha-synuclein (asyn) aggregates appear in the olfactory bulb and dorsal motor nucleus of the vagus (DMV) [3]. This concept immediately gave rise to the idea that PD pathology may in fact originate in synapses of the peripheral nervous system (PNS) and invade the brain from the olfactory epithelium and via retrograde axonal transport through the vagus, termed the dual-hit hypothesis [4]. This concept is supported by epidemiological evidence [5, 6] and the observation of pathological asyn aggregates in the PNS of PD patients up to 20 years prior to diagnosis [7–9].

Borghammer and van den Berge.

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis.

[aspergerian13 in reply to aspergerian13]

See also MBAnderson's post:

healthunlocked.com/parkinso....

[Rosenmu in reply to aspergerian13]

Thanks for bringing that back to attention. I'm wondering if there is anyone here that has improved their symptoms with reducing their inflammation? One of the articles talks a lot about inflammation. I'm currently working to get my inflammation down.

[Kimbo1962 in reply to Rosenmu]

Yes...my husband when gets inflammation parkinsons symptoms get so much worse. When he took prednisone cortisone he could almost walk normally again and movement was freed up. So reducing inflammation a huge issue. There is a new drug from a company called inflazomme that is currently being trialed. Watching to see.

[KERRINGTON in reply to Rosenmu]

Check out Sunvox's protocol. He has had success lately.

[Maltipom]

I don't remember ever having a since of smell. I really became aware of this during my preteens while playing games with friends that involved blind identification of tastes and smells.... I couldn't do it. The only person I ever told was my husband and of course my two daughters found this out as they growing up. My mother never had very good nose nor did my brother but father was a bloodhound. My first symptoms of Parkinson's were no swing in my left arm, a slight tremor I my left ring finger and stiffness in both legs. Go figure.

[1LittleWillow]

I had a head injury in 2003 (knocked unconscious, concussion). Within a few weeks, my sense of smell became disordered: I would smell things that weren't there, cookies would smell like menthol, bleach would smell like lavender, etc. At times my sense of smell was normal, and I didn't lose my ability to detect odors... they were just mixed up.

In mid-2015 I started to experience a slight weakness and lack of coordination in my left hand. It was rarely noticeable, so I didn't really think anything of it. I was still able to play the piano and the guitar at that time.

In January of 2018, I developed a twitch in the index finger of my left hand. Within a month it turned into a tremor and very obvious bradykinesia, and my sense of smell completely disappeared. By the time I was diagnosed in August of 2018, my left arm swing was gone, my left leg was dragging, I had a full-blown tremor in my left hand, arm, and leg, I was beginning to experience urinary urge incontinence, and I had severe insomnia. By November I was having memory issues and debilitating fatigue.

I have never had constipation issues and have never experienced any freezing episodes.

I don't take any PD meds yet. My neurologist wants me to, but I've declined them. I started taking thiamine HCL early November of 2018. My left arm swing is back to normal, my left leg drag is gone, the tremor in my left leg isn't as noticeable, the fatigue is about 80% better, urinary urge incontinence is gone, and my memory is fantastic. I still have tremor and bradykinesia in my left hand and almost no sense of smell.

[aspergerian13]

A very important anecdote. Splendidly informative.

[jeffreyn]

See also the PNT article about this research:

parkinsonsnewstoday.com/201...