Waste, Fraud, and Fish...

 

The high point of summers when I was a kid was fishing with my grandfather.  It was only about 4 or 5 hours but it was an adventure.  He had a 1933 Diamond-T flatbed truck that he used for his business that I have highlighted in a couple of places on this blog.  He also had a 14 ft. wooden boat built by the Peshtigo Boat Factory that he kept in immaculate condition.  He shellacked the interior and repainted the exterior every three years.  It always looked new.  He powered it with a 15 hp Johnson outboard motor.

Every fishing trip started the same way.  We put the boat and motor into the back of the Diamond-T, headed to the local bakery and picked up a dozen plain donuts or “fry cakes” as he would call them, and then drove out the Bad River where we put the boat in.  He knew several people with boat landings and occasionally we would just drop it in down a steep river bank from a dirt road.  We were always within a few miles on the upstream or downstream side of the U.S. Hwy 2 bridge.

Our fish of choice was walleye (Sander vitreus).  My grandfather’s preferred bait was June Bug spinners with nightcrawlers.  He and I usually used those with bait casting setups and 40 lb test nylon line.  The third person in the boat was a guest who in some cases would use exotic spin casting or spinning setups with many different artificial lures.  Bad River has a lot of snags and brush on the banks and that caused trouble for exotic lures cast great distances with monofilament line. 

We did not catch a lot of our preferred fish but there were plenty of other species to keep things interesting.   We typically caught and released them all except for the occasional walleye.  Between the fish biting we ate donuts and drank coffee.  There was always some kind of explanation for why we did not catch fish.  The water was too muddy or warm.  The river had been fished out with commercial gill nets. At one point there was talk of electrified nets and poison applied to catch or kill the sea lamprey (Petromyzon marinus). Sea lamprey are cartilaginous ancient parasitic fish that have been around for 340M years and survived all of the extinction events.  Before the advent of shipping canals in the mid-19^th century, Niagara Falls was a natural barrier to sea lamprey migration into the Great Lakes.  The first sea lamprey was discovered in Lake Superior in 1938 and in other Great Lakes earlier.  Sea lamprey have a devastating effect on the commercial and game fishery of the Great Lakes because of their reproductive success and success as a parasite.  Each lamprey can kill up to 40 lbs of game fish per year and reduce the fishing harvest to a fraction of what it should be.  The program to control sea lamprey is highly successful largely by controlling the larval forms that develop and migrate in various tributaries off the Great Lakes like Bad River.

What got me thinking about the sea lamprey again?  Over the past two days I was staying at a hotel on Lake Superior and noticed the parking lot had a small fleet of trucks from the US Fish and Wildlife Service (USFWS). Each pickup truck had SeaLampreyControl.org painted on the rear quarter panel.  When I saw all of these trucks, I was actively looking for the personnel driving them.  I was interested in how this program was able to survive the cuts of the Trump administration.   It seemed like an easy target.  Most people don’t know anything about the Great Lakes ecosystem or how it is scientifically monitored and managed.  Most people have no clue that as they are driving across Michigan’s upper peninsula and across northern Wisconsin into Minnesota that there are fishery biologists all along the way focused on that habitat and trying to keep it healthy.  The Trump administration has made it very clear that they don’t care about the environment or any of the associated science and in fact have open contempt for it.  But I was not able to find any of the staff driving those trucks so I decided to do my own research.  I have done limnology and freshwater biology and chemistry courses and research as an undergraduate – but this research was more straightforward.  I wanted to know if this program was a target of the Trump administration’s cuts.

The Department of Government Efficiency (DOGE) did target the U.S. Fish and Wildlife Service’s (USFWS) Sea Lamprey Control Program. In early 2025, 14 critical personnel (12 from USFWS and two from the U.S. Geological Survey(USGS)) were terminated right before the spring treatment cycle.  The Resolution highlights the fact that terminations and hiring freezes would reduce the lamprey control program by 1/3, leaving insufficient staff to implement the program and putting the Great Lakes fishery at great risk.  At least one reference states that the Trump administration was “ordered” to reinstate the fired workers (2).  Other sources suggest the cuts were potentially much larger and that Trump reversed them in January of 2026 by a bill. There is also supposed to be a paper trail of what happened in Congressional Committees and within the Department of the Interior / USFWS Memos.  But I can’t find any details about this.  I was eventually able to locate a press release about the firings and how they were reversed by court order.  The specific USFWS employees were mentioned (4).

My overall analysis based on limited information highlights the obvious lack of rational thinking. Before I had located any of the references, it seemed like the usual bad administrative exercise of just cutting an arbitrary number of people for the sake of making numbers. We know from DOGE headlines that this effort saved nowhere near the amount that they claimed and fired critical workers who had to be immediately rehired because the firings created a safety threat to the American people.  At first glance it seems like that is what happened to sea lamprey control. After the initial workforce reduction, the economic details presented in reference 1 were considered and the staff were rehired in order to prevent massive losses to the Great Lakes Fishery.  

But that is not what appears to have happened.  There was no rational thinking by the administration, only a legal technicality noted by a judge who said the administration does not have the power to fire staff from agencies outside the Executive Branch.  A Supreme Court decision eventually blocked reinstatement of probationary employees on a technicality.  So, no rational reversal of an irrational decision. To be clear, I am not sure that anyone knows the status of the fired employees from the USFWS and USGS.  I have sent an email to the USFWS to clarify what happened and I sked them specifically about whether sea lamprey control was at full strength.

My intent in writing this post is to focus squarely on the shortcomings of ideological decision making.  First, it short circuits rational decision making. Just looking at the economics – it makes no sense to stop a cost-effective government initiative that benefits a multibillion-dollar fishing and tourist industry.  That alone has value even without comparisons to how the current administration has squandered billions in tax dollars and continues to do so.  Second, the ethical dimension exists in the form of: “Is it ethical to stand by and watch the Great Lakes ecosystem destroyed and overrun by millions of parasitic fish?”  According to the numbers the sea lamprey is capable of this level of destruction.  The sea lamprey would not even be in the Great Lakes if it were not for government initiatives bypassing Niagara Falls allowing the initial migrations.  At that level sea lamprey and other invasive species are a manmade problem and it seems like a serious ethical lapse to not want to prevent that catastrophic outcome.

This is one small example of what happens when you have ideological myopia. Allowing the destruction of the Great Lakes ecosystem would be consistent with this administration's approach to climate science, medical care, and international aid all based on an alleged financial gain. It is essentially running a government that should have benefits for the people like running a business to produce benefits for only the favored few.  

It is hard to imagine a Great Lakes without Grandfathers and Grandchildren fishing.... 

 

George Dawson, MD, DFAPA

 

References:

1:  United States Committee of Advisors to the Great Lakes Fishery Commission. Resolution 25-01: A Resolution Calling for Full Support of the Great Lakes Sea Lamprey Control Program Including Full Restoration of Staff and an Exception to the Hiring Freeze in the United States to Implement the Critical Bi-National Control Program.  https://www.glfc.org/pubs/pdfs/resol2025_1.pdf

2:  Greco F.  U.S. firings reversed, yet Great Lakes Sea lamprey fight faces uphill battle.  CBC Lite April 4, 2025.  https://www.cbc.ca/lite/story/1.7501665

3:  Krumme M.  The invasive sea lamprey is poised for comeback in the Great Lakes.  Wisconsin Public Radio.  December 8, 2025. https://www.wpr.org/news/invasive-sea-lamprey-comeback-great-lakes-federal-funding

4:  Jenkins D.  Judge adds U.S. Fish and Wildlife to order curbing DOGE firings.  Capital Press.  March 3, 2025.  https://capitalpress.com/2025/03/03/judge-adds-u-s-fish-and-wildlife-to-order-curbing-doge-firings/

5:  Totenberg N, Gatti C.  Supreme Court lets Trump move forward with firing thousands of federal workers.  NPR News April 8, 2025.  https://www.npr.org/2025/04/08/nx-s1-5351799/scotus-probationary-workers

 

 

6:  Fritze J, Cole D Sneed T.  Supreme Court backs Trump for now on fired probationary federal employees.  CNN.  April 8, 2025.  https://www.cnn.com/2025/04/08/politics/probationary-fired-employees-supreme-court-trump

7:  Bijman V. The Sea Lamprey (Petromyzon marinus) Invasion: The Construction of an Invasive Animal Threatening a "Healthy" Great Lakes Ecosystem. J Hist Med Allied Sci. 2025 Oct 8;80(4):363-383. doi: 10.1093/jhmas/jrae046. PMID: 39889225; PMCID: PMC12504013.

“Although sea lamprey research, localized control practices, and environmental discourses considerably changed, the sea lamprey continued to be regarded as an invasive fish that was not allowed to exist in the Great Lakes.”

8:  Siefkes MJ. Use of physiological knowledge to control the invasive sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes. Conserv Physiol. 2017 May 30;5(1):cox031. doi: 10.1093/conphys/cox031. PMID: 28580146; PMCID: PMC5448140.

9:  Dale P. Burkett, Jessica M. Barber, Todd B. Steeves, Michael J. Siefkes, Sea lamprey control 2020 – 2040: Charting a course through dynamic waters, Journal of Great Lakes Research, Volume 47, Supplement 1, 2021, Pages S809-S814,

“Delivery of a successful Sea Lamprey Control Program depends upon bi-national, government-funded operations and research and is contingent upon public understanding of the need for the Program and its ecosystem and economic benefits. Changing social, political, regulatory, and climatological environments present a host of strengths, weaknesses, opportunities, and threats requiring an array of responses.”

10:  F.B. Neave, R.M.W. Booth, R.R. Philipps, D.A. Keffer, G.A. Bravener, N. Coombs,  Changes in native lamprey populations in the Great Lakes since the onset of sea lamprey (Petromyzon marinus) control, Journal of Great Lakes Research, Volume 47, Supplement 1, 2021, Pages S378-S387,

The control of invasive sea lamprey in the Great Lakes basin has been highly successful, but has deleteriously affected native lamprey species. American brook, northern brook, silver and chestnut lampreys are all susceptible to lampricide treatments.

 

Supplementary 1:  It is widely known that Freud studied eels as a young biologist and in that process also studied the nervous system of the sea lamprey.

Supplementary 2:  The sea lamprey pesticides:  Are they toxic to dopaminergic neurons? 

TFM and Bayluscide, are specialized pesticides called lampricides. These are applied by agencies like the Great Lakes Fishery Commission to targeted streams and tributaries where young lamprey larvae hatch and develop.

 

• TFM (3-trifluoromethyl-4'-nitrophenol): This is the most widely used lampricide. It is a selective poison that disrupts the energy metabolism (mitochondrial decoupling) of sea lampreys at concentrations that leave most other native fish and organisms unharmed. Lampreys have a reduced capacity to detoxify the chemical.

 

• Bayluscide (niclosamide): Highly toxic lampricide that is often used in combination with TFM. By adding a small amount of Bayluscide to TFM, agencies can reduce the overall amount of chemical needed, keeping treatment methods highly effective and lowering costs. A granular time-release form is also used to treat deep, slow-moving waters or estuaries where TFM is less effective.

 

Both chemicals are regulated restricted-use pesticides that break down naturally in the environment and do not bioaccumulate.  Niclosamide has been suggested as a treatment for neurodegenerative disorders including Parkinsons and it a potential neuroprotectant:

 

Apolloni S, D'Ambrosi N. Repurposing niclosamide for the treatment of neurological disorders. Neural Regen Res. 2023 Dec;18(12):2705-2706. doi: 10.4103/1673-5374.373705. PMID: 37449632; PMCID: PMC10358648.

 

Disenrollment And Payment Suspension To Minnesota Health Care Providers MHCPs)...

 

Inspection of the above timeline shows how the second wave of Operation Metro Surge in the Twin Cities was coordinated with a crackdown on suspected health care benefits fraud that was attributed to undocumented communities.  The threat to withhold funding was based on that unsubstantiated hypothesis.  The Trump administration used a coordinated threat narrative tying “open border” immigration policy to fraud exploiting public systems.  It is a familiar “the unworthy are stealing your tax dollars” political rhetoric.   The coordinated threat narrative—which claimed that local "open-border" policies directly enabled massive Medicaid and pandemic welfare fraud rings—collapsed under legal and factual scrutiny.  The vast majority of an estimated 3,000-4,000 immigration arrests were not linked to health care fraud.  The people charged were US citizens. The Metro Surge itself caused $700M in economic damage and lost economic activity.  It also cost taxpayers an estimated $18M per week.  In other words the financial cost of the operation was much more than the fraud detected but far beyond that there were the lives lost in the process.    

There was a recent massive disenrollment of Minnesota Health Care providers (MHCPs).  By definition these are health care providers funded by Medicaid (Medical Assistance, or MA) and MinnesotaCare.  Each one of these providers has a portal to the state that enables direct payment for services.  The Minnesota Department of Human Services (DHS) has disenrolled 3,411 out of nearly 5,600 reviewed "high-risk" Medicaid providers. These providers have had their Minnesota Health Care Programs (MHCP) payments immediately cut off. Disenrolled entities have 60 days to appeal their removal (1).  Unless they have a successful appeal they can no longer bill Medicaid.

Minnesota identifies “high risk providers” as belonging to the following 14 categories (2):

1. Early Intensive Developmental and Behavioral Intervention (EIDBI): Autism therapy and developmental services for children.
2. Adult Companion Services: Non-medical care, socialization, and supervision for adults.
3. Adult Day Services: Structured community-based programs offering health and social services.
4. Adult Rehabilitative Mental Health Services (ARMHS): Mental health services focused on instructing and supporting independent living skills.
5. Assertive Community Treatment (ACT): Intensive, comprehensive community-based outreach and treatment for severe mental illness.
6. Community First Services and Supports (CFSS): Assistance with activities of daily living and health-related tasks.
7. Individualized Home Supports (IHS): Support provided in a person’s own home or community to build independent living skills.
8. Integrated Community Supports (ICS): Multi-tenant housing support services for individuals with disabilities.
9. Intensive Residential Treatment Services (IRTS): Time-limited, 24/7 mental health treatment in a residential setting.
10. Night Supervision Services: Overnight monitoring and assistance in a person's home.
11. Nonemergency Medical Transportation Services (NEMT): Transportation for medical appointments and services.
12. Peer Recovery Support Services: Substance use disorder support provided by individuals with lived recovery experience.
13. Recuperative Care: Medical care and support for individuals experiencing homelessness who are too ill to live on the street.
14. Housing Stabilization Services:  Consult and develop a housing plan for individuals without a case manager and support transition and stabilization in that setting.

 

  As a former acute care and inpatient psychiatrist at least 4 of these services (3,4,5, and 9) were critical in discharge planning for hospitalized patients.  That could mean the difference between a timely discharge and either no discharge or a suboptimal plan.  These resources are clearly in place for assisting disabled persons with few resources.  The Trump administration has already prioritized tax cuts for the wealthy over health care for the disabled and low-income adults most notably by cutting an estimated $1 trillion in Medicaid spending over the next 10 years. Much of those cuts are backloaded into the last 5 years of the bill.  As estimated 10 million people will lose healthcare coverage.  

The threatened cuts to Minnesota apparently occurred on the basis that the Trump administration Centers for Medicare and Medicaid Services (CMS) demanded the state implement a corrective action plan and they threatened to withhold up to $2 billion in Medicaid funding and froze over $200 million in payments. There are clear problems with that idea at the both the local and federal levels. 

The first problem is the determination of waste, fraud, and abuse in Minnesota.  How is it measured and are there any problems with the metrics?   CMS does keep ongoing records for Improper Payment Rates by year.  From the CMS page for the 2025 report just released:

“The Medicaid estimated improper average payment rate (comprised of the past three cycles of approximately 17 states per cycle from reviews in 2023, 2024, and 2025) was 6.12%, or $37.39 billion, compared to the FY 2024 reported rate of 5.09%, or $31.10 billion. Of the FY 2025 Medicaid improper payments, 77.17% were the result of insufficient documentation, which is generally not indicative of fraud or abuse.”

The improper payment rates for Medicaid/CHIPS in Minnesota was 2.2% in both 2022 and 2025 – the most recent years surveyed.  That compares to a nationwide average improper payment rate of 15.62% and 6.12% respectively.  It is also below a national threshold established in H.R. 1 of 3% for financial penalties that will apply to all states starting in 2030.  The author of this article (dated January 30, 2026) clearly states that this indicates the action against Minnesota is partisan (1).

All of this occurs in the context of unprecedented personal and political attacks by President Trump and his cabinet.  Waste, fraud, and abuse is one of their common attacks.  It was the basis for the initial DOGE purges of 300,000 federal employees, that saved no money, eliminated considerable expertise and institutional knowledge and impacted the safety of the American people to the point that 25,000 had to be called back immediately.  The firings include 40,000 VA employees including 3,000 nurses and 1,000 physicians.  Part of those firings included 17 Inspector Generals whose job it is to determine waste, fraud, and abuse.  A subsequent report showed that the effects of the Inspectors General on waste, fraud, and abuse dwarfed the impact of DOGE. It is remarkable that the main selling points of DOGE were gross exaggerations of waste, fraud, and abuse. The goal of 1-2 trillion in savings was unrealistic from the outset.  At one point the White House spokesperson and Elon Musk both claimed that $2.7 trillion in Medicaid and Medicare benefits had been diverted to foreign nationals overseas.  In actual fact this was an estimate of improper payments by numerous government agencies since 2003. 

Apart from the lack of government savings and efficiency, destruction of government infrastructure, and destruction of federal employee morale – there has been a massive human cost that is hardly mentioned in the United States. Defunding USAID and PEPFAR will result in an estimated 500,000 to 1,000,000 deaths annually, 4.2 million deaths due to AIDS, and as many as 14.1 million deaths by 2030.  The excess mortality will primarily be from AIDS, malaria, tuberculosis, nutritional deficiencies, and diarrheal diseases (4).  

To be clear, fraud is always occurring at some level whether it is government programs or internet schemes designed to steal money from citizens. There are no fraud free zones in the United States and the protections for private citizens are minimal. Medicaid Fraud Control Units under the Inspector General are charged with investigating fraud and recovering money if possible.  Since Medicaid is a joint federal and state program each state also has an Inspector General or Medicaid Fraud Control Unit (MFCU).

It should be clear to any objective observer that rage and faux rage are all part of the Trump and MAGA ethos.  It is more commonly referred to as bullying and intimidation directed at anyone Trump dislikes.  Waste, fraud, and abuse is their war cry despite the fact that Trump has granted clemency to persons who have been convicted of fraud and in many cases ordered to pay penalties and restitution for a total of $2 billion. That is over $2 billion just excused by an administration who claims to be concerned with fraud.

That is what is really going on in Minnesota.  It is the only explanation for the great precipitous disenrollment of MHCP providers and Vance’s latest demand to investigate the Governor and Attorney General for “fraud”.  This pattern will continue until this contentious government is either voted out or shut down by Congress or the Judicial branch.      

 

George Dawson, MD, DFAPA

 

References:

1:  Schneider A.  CMS Quietly Releases Medicaid State Improper Payment Rates for 2025: How Did Minnesota Do?.  January 30, 2026  https://ccf.georgetown.edu/2026/01/30/cms-quietly-releases-medicaid-state-improper-payment-rates-for-2025-how-did-minnesota-do/

2:  Clemency Grants by President Donald J. Trump (2025-Present).  Office of the Pardon Attorney:  https://www.justice.gov/pardon/clemency-grants-president-donald-j-trump-2025-present

3:  Minnesota Litigation Tracker (Attorney General Web Site).  Minnesota is currently or was a party in 61 lawsuits against the federal government. https://www.ag.state.mn.us/Rule-Of-Law/Litigation/

4:  Cavalcanti D, de Oliveira Ferreira de Sales L, da Silva A et al.  Evaluating the impact of two decades of USAID interventions and projecting the effects of defunding on mortality up to 2030: a retrospective impact evaluation and forecasting analysis.  The Lancet, 2025; 406, 283-29  https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01186-9/fulltext

 5:  Karcher-Ramos M.  Housing, Jobs and the Local Economy: Operation Metro Surge’s Long-term Impacts to People and Prosperity in Minnesota.  McKnight Foundation News. https://www.mcknight.org/news-ideas/economic-impact-operation-metro-surge/

6:  Ellie Roth.  DHS disenrolls 3,400 Medicaid providers while flagging small fraction for further fraud review.  MPR.  June 4, 2026.  https://www.mprnews.org/story/2026/06/04/dhs-disenrolls-3400-medicaid-providers-while-flagging-small-fraction-for-further-fraud-review

7:  Medicaid Program Integrity.  Minnesota Department of Human Services.  https://mn.gov/dhs/program-integrity/

 

 

Supplementary 1:  Lawsuits between states and the federal government under each administration

Presidential Administration	Total Multistate Lawsuits Filed by States
Ronald Reagan (1981–1989)	15 lawsuits
George H.W. Bush (1989–1993)	8 lawsuits
Bill Clinton (1993–2001)	18 lawsuits
George W. Bush (2001–2009)	76 lawsuits
Barack Obama (2009–2017)	78 lawsuits
Donald Trump (First Term) (2017–2021)	138 lawsuits
Joe Biden (2021–2025)	Approximately 100 lawsuits
Donald Trump (Second Term) (2025–Present)	100 in the first 18 months

 

Supplementary 2:  I received the following notice by email today from the Minnesota Department of Human Services.  My interpretation of it is that they are seeking to provide relief to providers by lifting the payment suspension based on an appeal.  This is obviously one small part of a massive and unnecessary drama initiated by the Trump administration. 

Lessons For Psychiatry From a Recent Review of Parkinson's

 

Movement disorders have always been an area of fascination for me.  There is overlap with many neuropsychiatric disorders and people with movement disorders develop neuropsychiatric disorders.  Early in my career it was common to see people with tardive dyskinesia and other medication or street drug induced movement disorders (akathisia, chorea, Parkinson’s, dystonia, oculogyric crises).  In acute care psychiatry it was one of the more distressing parts of the practice. It was possible to discharge stabilized patient from the hospital and by the time you saw them in follow up a couple of weeks later they could have developed tardive dyskinesia.  If you worked on an acute care unit – people with tardive dyskinesia were routinely seen.  That nearly resolved with the advent of a new generation of dopamine receptor antagonist antipsychotics.

Over my first decade of practice the only strategies available to treat tardive dyskinesia or medication exposure syndromes was stopping the medication or reducing it to the lowest possible dose. The was always preceded by a detailed informed consent discussion including the possibility that the primary symptoms would recur. I cannot recall a person who wanted to discontinue the medication based on that discussion.  All were aware that the movement symptoms were caused by the medication but they did not want recurrent psychiatric symptoms.

The only available treatment at the time was tetrabenazine but people had to travel to Canada to get a prescription.  Clozapine revolutionized the treatment for many people because it invariably treated or stopped the movement disorder and treated he psychiatric symptoms (1,2). There was a brief period of time when low dose antipsychotics like thioridazine were suggested as a possible treatment – but it was clear there were no advantages and potentially an additional side effect of prolonged QTc interval on ECG and arrhythmia.

In my second decade of practice, I was involved with a Memory Disorder and Geriatric Psychiatry Clinic.  We were referred many elderly patients with movement disorders.  Two of the commonest scenarios was a patient with a history of bipolar disorder, depression, or schizophrenia who developed Parkinson’s Disease in their 60s and the Parkinson’s patient who developed delirium or psychosis from taking medication for the movement disorder.  At the time clozapine was still tightly regulated because it was costly and required an intensive monitoring system.  In order to prescribe it there was a prior authorization system through the state and they only approved it for the FDA indication at the time – treatment resistant schizophrenia.  I had to show that the patient had been treated with two other antipsychotics in adequate doses.

One of the most striking presentations of Parkinson’s I saw during that time was an elderly woman with what I diagnosed as tardive Parkinson’s (3).  She had a preexisting psychosis and ongoing florid delusional symptoms, bradykinesia, hypophonic dysarthria, axial rigidity, and severe gait disturbance. She improved significantly with clozapine.

Like all diseases, the presentation of movement disorders vary significantly from person to person.  In the case of Parkinson’s and psychiatry – learning to diagnose parkinsonism at the earliest possible stage is a required skill when prescribing dopamine receptor antagonists (DRAs). Learning the clinical picture of hyperkinetic and hypokinetic movement disorders was also useful.  That led me to be a member of the Movement Disorder Society (MDS) and attend the Aspen Movement Disorders course for many years.  As a member of MDS – I got the journal Movement Disorders and video of the cases discussed initially on tape and then CDs.  Movement Disorders is a very high-quality journal and by reading I always learned valuable details like clozapine being the only DRA that does not make Parkinson’s worse and it could be used to treat resistant tremor in the disorder. 

When I saw this open access review of Parkinson’s in Movement Disorders (4) – I knew I had to read it.  Historically Parkinson’s has always been presented as a disease of the substantia nigra – a critical part of the basal ganglia containing dopaminergic neurons. The dopaminergic neurons deteriorate and die off and at a certain critical point the signs and symptoms of Parkinson’s occur.  That implies that the underlying pathophysiological process has been going on for some time before the patient becomes symptomatic.  The genetics and some environmental causes were relevant.  In this case there was also an infectious cause – von Economo’s encephalitis.  In medical school in the 1980s there were still some survivors of that epidemic.  Although both diseases affect the substantia nigra Parkinson’s is technically a synucleinopathy and post-encephalitic parkinsonism (PEP) is a tauopathy.

Parkinson’s disease and various forms of parkinsonism are proteinopathies caused by misfolded protein aggregates in this case hyperphosphorylated tau protein (PEP) and α-synuclein (Parkinson’s).  Proteinopathies can be caused by a number of factors that often converge including genetics (mutations leading to abnormal proteins), deteriorated protein quality control with aging (5,6), oxidative stress, prion-like propagation (7), post translational modifications (8), and unstable protein structures. 

Long before these mechanisms were discovered epidemiological associations between Parkinson’s disease and parkinsonism were noted with heavy metals, industrial solvents, pesticides, and air pollution (9).  There are also miscellaneous toxins like MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) – a contaminant produced in the illicit manufacture of meperidine that can cause Parkinson’s.  A partial list is contained in the table below:

 

Toxin	Class	Year First Linked to PD or Parkinsonism	Strength of Evidence	References
Manganese	Heavy metal	1837	Strong (direct cause of manganism)	[1-2]
Carbon monoxide	Gas	Early 20th century	Strong (direct cause)	[3]
Carbon disulfide	Solvent	Mid-20th century / 1981	Moderate	[3-4]
Mercury	Heavy metal	1981	Inconsistent	[4-5]
MPTP	Synthetic contaminant	1983	Definitive (direct cause)	[6-7]
Paraquat	Herbicide	Late 1980s–1990s	Strong	[8-9]
Organochlorines (dieldrin, heptachlor, chlorpyrifos)	Pesticides	1989–1999 (meta-analyses)	Moderate–Strong	[10-11]
Rotenone	Insecticide	Early 2000s	Strong	[9]
Agent Orange / dioxin	Herbicide, contaminant	1990s–2000s	Sufficient (per National Academies)	[12-13]
Maneb / dithiocarbamates	Fungicides	2000s	Moderate	[14]
TCE (Trichloroethylene)	Solvent	2012	Strong (growing)	[15]
PCE (Perchloroethylene / Tetrachloroethylene)	Solvent	2010s	Moderate	[16-17]
Air pollution (PM2.5)	Ambient	~2018	Moderate (emerging)	[18-20]
Iron, lead, copper, aluminum	Heavy metals	1980s–1990s	Inconsistent	[21-22]
Methamphetamine, amphetamine	Non-therapeutic	2015-2016	Moderate	[14, 23-24]
1: Dorsey ER, De Miranda BR, Hussain S, Bloem BR, Elbaz A, Llibre-Guerra J, Lo RY, Goldman SM, Tanner CM. Environmental toxicants and Parkinson's disease: recent evidence, risks, and prevention opportunities. Lancet Neurol. 2025 Nov;24(11):976-986. doi: 10.1016/S1474-4422(25)00287-X. PMID: 41109237.  2: McKnight S, Hack N. Toxin-Induced Parkinsonism. Neurol Clin. 2020 Nov;38(4):853-865. doi: 10.1016/j.ncl.2020.08.003. Epub 2020 Sep 9. PMID: 33040865.  3:  Blanc PD. The early history of manganese and the recognition of its neurotoxicity, 1837-1936. Neurotoxicology. 2018 Jan;64:5-11. doi: 10.1016/j.neuro.2017.04.006. Epub 2017 Apr 14. PMID: 28416395.  4:  Racette BA, Aschner M, Guilarte TR, Dydak U, Criswell SR, Zheng W. Pathophysiology of manganese-associated neurotoxicity. Neurotoxicology. 2012 Aug;33(4):881-6. doi: 10.1016/j.neuro.2011.12.010. Epub 2011 Dec 21. PMID: 22202748; PMCID:  PMC3350837.  5:  Miranda M, Bustamante ML, Mena F, Lees A. Original footage of the Chilean miners with manganism published in Neurology in 1967. Neurology. 2015 Dec 15;85(24):2166-9. doi: 10.1212/WNL.0000000000002223. PMID: 26668239.  6:  Ohlson CG, Hogstedt C. Parkinson's disease and occupational exposure to organic solvents, agricultural chemicals and mercury--a case-referent study. Scand J Work Environ Health. 1981 Dec;7(4):252-6. doi: 10.5271/sjweh.2549. PMID: 7347910.  7:  Cariccio VL, Samà A, Bramanti P, Mazzon E. Mercury Involvement in Neuronal Damage and in Neurodegenerative Diseases. Biol Trace Elem Res. 2019 Feb;187(2):341-356. doi: 10.1007/s12011-018-1380-4. Epub 2018 May 18. PMID: 29777524.  8:  Ganguly J, Kulshreshtha D, Jog M. Mercury and Movement Disorders: The Toxic Legacy Continues. Can J Neurol Sci. 2022 Jul;49(4):493-501. doi: 10.1017/cjn.2021.146. Epub 2021 Jun 24. PMID: 34346303.  9:  de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006 Jun;5(6):525-35. doi: 10.1016/S1474-4422(06)70471-9. PMID: 16713924. 10:  Bjorklund G, Stejskal V, Urbina MA, Dadar M, Chirumbolo S, Mutter J. Metals and Parkinson's Disease: Mechanisms and Biochemical Processes. Curr Med Chem. 2018;25(19):2198-2214. doi: 10.2174/0929867325666171129124616. PMID: 29189118. 11:  Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet. 2004 May 29;363(9423):1783-93. doi: 10.1016/S0140-6736(04)16305-8. PMID: 15172778. 12:  Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4546-50. doi: 10.1073/pnas.80.14.4546. PMID: 6192438; PMCID: PMC384076. 13:  Varçin M, Bentea E, Michotte Y, Sarre S. Oxidative stress in genetic mouse models of Parkinson's disease. Oxid Med Cell Longev. 2012;2012:624925. doi: 10.1155/2012/624925. Epub 2012 Jul 8. PMID: 22829959; PMCID: PMC3399377. 14:  Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 2016 Nov;15(12):1257-1272. doi: 10.1016/S1474-4422(16)30230-7. Epub 2016 Oct 11. PMID: 27751556. 15:  Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR, Comyns K, Richards MB, Meng C, Priestley B, Fernandez HH, Cambi F, Umbach DM, Blair A, Sandler DP, Langston JW. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect. 2011 Jun;119(6):866-72. doi: 10.1289/ehp.1002839. Epub 2011 Jan 26. PMID: 21269927; PMCID: PMC3114824. 16:  Weisskopf MG, Knekt P, O'Reilly EJ, Lyytinen J, Reunanen A, Laden F, Altshul L, Ascherio A. Persistent organochlorine pesticides in serum and risk of Parkinson disease. Neurology. 2010 Mar 30;74(13):1055-61. doi: 10.1212/WNL.0b013e3181d76a93. PMID: 20350979; PMCID: PMC2848105. 17: Ross GW, Abbott RD, Petrovitch H, Duda JE, Tanner CM, Zarow C, Uyehara-Lock JH, Masaki KH, Launer LJ, Studabaker WB, White LR. Association of brain heptachlor epoxide and other organochlorine compounds with lewy pathology. Mov Disord. 2019 Feb;34(2):228-235. doi: 10.1002/mds.27594. Epub 2018 Dec 30. PMID: 30597605; PMCID: PMC6602549. 18:  Tanner CM, Ostrem JL. Parkinson's Disease. N Engl J Med. 2024 Aug 1;391(5):442-452. doi: 10.1056/NEJMra2401857. PMID: 39083773. 19:  Pouchieu C, Piel C, Carles C, Gruber A, Helmer C, Tual S, Marcotullio E, Lebailly P, Baldi I. Pesticide use in agriculture and Parkinson's disease in the AGRICAN cohort study. Int J Epidemiol. 2018 Feb 1;47(1):299-310. doi: 10.1093/ije/dyx225. PMID: 29136149. 20:  Goldman SM, Weaver FM, Stroupe KT, et al. Risk of Parkinson Disease Among Service Members at Marine Corps Base Camp Lejeune. JAMA Neurol. 2023;80(7):673–681. doi:10.1001/jamaneurol.2023.1168 21:  Frumkin H. Multiple system atrophy following chronic carbon disulfide exposure. Environ Health Perspect. 1998 Sep;106(9):611-3. doi: 10.1289/ehp.98106611. PMID: 9721261; PMCID: PMC1533160. 22:  Hageman G, van der Hoek J, van Hout M, van der Laan G, Steur EJ, de Bruin W, Herholz K. Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure. J Neurol. 1999 Mar;246(3):198-206. doi: 10.1007/s004150050334. PMID: 10323318. 23:  Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR. Methamphetamine/amphetamine abuse and risk of Parkinson's disease in Utah: a population-based assessment. Drug Alcohol Depend. 2015 Jan 1;146:30-8. doi: 10.1016/j.drugalcdep.2014.10.027. Epub 2014 Nov 16. PMID: 25479916; PMCID: PMC4295903. 24: Lappin JM, Darke S. Methamphetamine and heightened risk for early-onset stroke and Parkinson's disease: A review. Exp Neurol. 2021 Sep;343:113793. doi: 10.1016/j.expneurol.2021.113793. Epub 2021 Jun 21. PMID: 34166684.

 

When I say partial list the evidence for environmental toxins is still accumulating.  For example, a study recently showed a correlation between the incidence of Parkinson’s Disease and proximity to a golf course (10).  Groundwater contamination was considered the primary source of toxicity.  Interestingly American golf courses apply pesticides at 15 times the rate of European golf courses.

Quite amazingly there is no screening for dopaminergic neuron toxicity before or after insecticides, fungicides, and rodenticides are marketed.  Screening methods are currently being developed (11,12) but the applications of these compounds are widespread.  In the late spring I can look out of my office window and see herbicides and pesticides being applied to every lawn and garden in my neighborhood. 

Widespread use of these compounds and other contaminants is associated with a significant increase in the incidence and prevalence of Parkinson’s Disease. Global cases are estimated to double over the next 25 years from 11.8M to 25.2M (13). The main factors driving this increase are twofold – an aging demographic (people over the age of 60 are at higher risk) and environmental toxins.

While most people worry about Alzheimer’s Disease the fastest growing neurodegenerative condition is Parkinson’s Disease. At this point we probably lack precision in the best way to prevent it.  Much more attention needs to be paid to every day neurotoxins in the environment at the individual level. Do you have some in your garage?  Do you walk into the house with the same shoes you were wearing in the garage?  Can the residues of some of these toxins sublimate or evaporate in the garage leading to their inhalation?  Do people with attached garages have a higher risk?  How should your drinking water be analyzed?  These are some environmental questions that have not been answered.

I will digress into a little physical chemistry at this point before I wrap up with the Parkinson’s paper and the observation of proteinopathies.  The paper focuses on 4 proteins TDP-43, beta amyloid, tau, and α-synuclein.  I have included them in a table about some of their basic properties (click to enlarge).

There are a few relevant concepts from the perspective of chemistry.  The first is that the molecules of interest are all large protein molecules (14-43 kilodaltons).  The genetics of the proteins are all known and, in some cases, the total number of mutations producing altered proteins is known.  All of the proteins have roles in normal physiology.  All can be condensed into an amyloid state with a characteristic hydrogen bonded fibril structure.

These proteins are also known as intrinsically disordered proteins (IDP) meaning they do not spontaneously fold into a stable 3-dimensional structure in physiological conditions but still carry out physiological functions.  This is a challenge to Anfinsen’s dogma that states a unique stable protein structure at the lowest Gibbs free energy state is necessary for physiological function.   IDPs thus have ensembles of conformations rather than a single best one. They tend to be highly charged molecules with more ionic residues, preventing lipophilic collapse to a single state.  They remain functional by binding mechanisms and changing conformation after binding.      

In the table, tau, Aβ and α-synuclein are fully disordered IDP.   TDP-43 and PrP are hybrid proteins containing both folded domains and IDR (intrinsically disordered regions).  In the above table Aβ is a cleavage product and not an IDP/IDR.  The abbreviated diseases listed in column 5 are all proteinopathies – reflecting the pathophysiology of the underlying proteins.

In the review the authors emphasize that rather than a prototypical synucleinopathy most people with Parkinson’s have additional pathologies that may affect the course and features of the illness.  The  synucleinopathies include Parkinson’s Disease PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).  They discuss hypotheses about how synuclein is initiated in the nervous systema nd how it spreads:

The Braak hypothesis suggests the disease begins in the enteric plexus then enters the lower brainstem and eventually the cortex.  Alternately the disease begins in the olfactory bulb and spread in a rostral to caudal direction in the brain.  The Unified Staging System of Lewy Body Disorders suggests the disease begins in the olfactory bulbs and spreads to the limbic system or brainstem.  The α-synuclein origin site and connectome model (SOC) suggests a combination of both of those models. The brain first verses body-first hypotheses attempts to account for the observation that no matter where the pathology starts it spreads through the brain via the connectome by purported prion like mechanisms. 

Promising biomarkers have been identified to assist in studying the pathology.  Phosphorylated synuclein in peripheral nerves is thought to mirror brain synuclein.  I am aware of some patients who were diagnosed with Parkinson’s Disease who have had peripheral nerve biopsies that were negative for synuclein.  Positron emission tomography (PET) imaging is available for tau and amyloid-β (Aβ) at some centers and there are currently studies looking at ligands for α-synuclein.  Assays developed for prion diseases may be adapted to test for α-synuclein and other misfolded proteins in the blood and CSF. 

The graphic at the top of this post depicts the co-occurring pathologies in Parkinson’s.  These copathologies correlate with more cognitive impairment and greater disease severity.  The authors suggest that the evidence is compelling enough to reconceptualize PD as a disease of copathologies rather than a pure synucleinopathy.  The authors examine the implications of these copathologies in PD in great detail.  Tau in the substantia nigra alone can lead to gait disturbances.  Patients with PD who have tau in their CSF are more likely to develop dementia.  Patients with pathology of both AD and DLB are more likely to have faster disease progression. 

Aβ plaques are commonly found in patients with PD and the prevalence increases with age.  Total plaque burden correlates with progression to dementia and time between onset of motor symptoms and onset of dementia. 

TDP-43 in the substantia nigra has been linked to PD even without synuclein.  It typically aggregates in the entorhinal cortex and amygdala in Lewy Body disorders.  TDP-43 seems to have the lowest rates of copathology and in general raise the concern of may of these accompanying lesions – what concentrations and locations are clinically relevant.   

The authors look at the issue of small vessel disease (SVD), how it is prevalent in PD and how the underlying disease process may be involved in addition to the usual risk factors.  PD patients have about twice the number of white matter hyperintensities compared to age matched controls.  Alpha-synuclein cause a vasculopathy (14) by depositing in the arterial endothelium leading to blood-brain barrier (BBB) damage, endothelial dysfunction, and structural damage to brain capillaries.  The resulting oxidative stress and mitochondrial damage creates a cascade effect across multiple cell types leading to rapid disease progression.

The authors discuss some of the variation in monogenic forms of PD.  They present a table with 16 genotypes and the type of proteinopathy found.  There is every possible combination of proteins found in clinically symptomatic patients. They point out the limitations based on small numbers of patient studied.

In discussing the genetics, the authors point out: “It has been proven that overlapping neurological disorders share common genetic loci.” (p. 8) and the comorbidities in this case suggest “pleiotropy of pathological mechanisms.”  They discuss some of the common genetics between PD and the other proteinopathies.  In the final section they discuss inflammation as a non-neuronal process that drives the pathology.  Overall this is an excellent review of PD at the physiological level and because it is available free online, I encourage anyone interested to read it.

What does all of this have to do with psychiatry?  Am I just an unusual psychiatrist who should have been a neurologist or a neurosurgeon?  I suggest a few things:

1:  This information needs to be in the DSM – yes, it always seems to come back to the DSM.  After all the DSM has an entire chapter of Neurocognitive Disorders that names all of the disorders listed in this post.  Is it going to incorporate some of the latest findings in the field or remain vague.  There are currently 3 pages about Major or Mild Neurocognitive Disorder due to Parkinson’s disease.

2:  Heterogeneity - I love the smell of heterogeneity in the morning.  Let’s face it for the past 40 years of my career our understanding of Parkinson’s has gone from a basic lesion in the substantia nigra of unknown etiology to a mix of proteinopathies moving in the brain like prions.  And further the authors of this review point out that like a lot of neurological disorders there are probably common genetic loci.  Well past the time to stop apologizing for heterogeneous and genetically common disorders in psychiatry.  At one point in this reading, I had the fantasy of what the network diagrammers would do in this case connecting all of the symptom and pathology nodes and talking about transdiagnostic features.  Should we try to make a network of all of those signs, symptoms and pathologies and see what we come up with?  Probably not.  

3:  Training – training in all of this brain specific pathology and genetics is important for psychiatric residents and psychiatrists.  We cannot be focused on a transdiagnostic dementia diagnosis based on clinical features and ignore the brain biology.  That brain biology is exactly why no two patients with these disorders will be alike.  Psychiatrists will be seeing diagnosed and undiagnosed, treated and untreated PD and parkinsonism.  It is not acceptable to miss that diagnosis or realize how your psychiatric treatment would affect the diagnosis or treatment of PD.

4:  Advocacy and public health – it should be shocking to anyone that chemicals used to poison plants, insects, and rodents are not routinely screened for their toxicity to dopaminergic neurons.  If your neighborhood is anything like mine – they are massively applied.  Even if it is not, what about public areas like parks and recreational areas?  Is there any good reason that American golf courses get 15 times as many pesticides and European golf courses?  It is equally shocking that toxins that probably cause this toxicity are not immediately pulled from the market.  An epidemic of Parkinson’s Disease is too high a price to pay for a weed free lawn.  

5:  The vasculopathy associated with synuclein was a surprise – I am an advocate for risk factor reduction for all forms of cardiovascular disease. I am not aware of any study that looks at how people with that orientation do if they have PD or more specifically α-synuclein associated PD.  That seems like a necessary study.

6: Phenotypes – all of the pathophysiology described does not readily lend itself to stable phenotypes.  Attempts at subtyping Parkinson’s based on clinical features like tremor, posture and gait instability, akinesia and rigidity, or mixed features is relatively recent development.  In that study one phenotype can change into another (15).  In another analysis (16,17) phenotypes based on presentation, medication responsiveness, and progression seem to reflect disease progression more than stable phenotypes.  This is another lesson for the psychiatric controversy about disease overlap and transdiagnostic symptoms.  In this case we have four identifiable proteinopathies spreading like infectious particles through the connectome.  Would we expect network-based disorders to be any easier to characterize?  It also answers the age-old question: “Is a single pathophysiological defect necessary to characterize a disease?”  At least if Sydenham had not answered it nearly 4 centuries ago.   

That is about all I can think of saying about this post.  I may add a few things in the future.  I am currently awaiting a paper that describes the chemistry and thermodynamics of IDPs (intrinsically disordered proteins) and (intrinsically disordered regions) IDRs. This information likely has implications for the clinical course and treatment of people with this disorder.  If I can find enough of that information, I will probably try a separate post.  At the time of this writing, I am not aware of any specific treatments for proteinopathies or the prion like spread of the disorder suggested in this review.  

 

George Dawson, MD, DFAPA

Graphics Credit:  The lead graphic for this post is from reference 4 - per the following This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, CC BY-NC-ND 4.0 which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

It is unmodified and this is a not-for-profit and non-commercial blog.

Both tables were made by me.

Supplementary:

This paper on diet and Parkinson's is open access from Movement Disorders.  It shows that diet may not be a significant factor relative to other environmental and genetic factors.  8 healthy dietary patterns were examined the the quintile with the highest adherence was compared to the quintile with the lowest adherence.  Higher low fat dairy intake was associated with higher Parkinson's risk. 

Chen X, Chen H, Wang P, Schwarzschild MA, Hung AY, Gao X, Ascherio A, Flores-Torres MH, Bjornevik K. Healthy Dietary Patterns and Risk of Parkinson's Disease. Mov Disord. 2026 Jun 4. doi: 10.1002/mds.70358. Epub ahead of print. PMID: 42237654.

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2:  Lee D, Baek JH, Bae M, Choi Y, Hong KS. Long-Term Response to Clozapine and Its Clinical Correlates in the Treatment of Tardive Movement Syndromes: A Naturalistic Observational Study in Patients With Psychotic Disorders. J Clin Psychopharmacol. 2019 Nov/Dec;39(6):591-596. doi: 10.1097/JCP.0000000000001114. PMID: 31688397.

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5: Gandhi J, Antonelli AC, Afridi A, Vatsia S, Joshi G, Romanov V, Murray IVJ, Khan SA. Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics. Rev Neurosci. 2019 May 27;30(4):339-358. doi: 10.1515/revneuro-2016-0035. PMID: 30742586.

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9:  Dorsey ER, De Miranda BR, Hussain S, Bloem BR, Elbaz A, Llibre-Guerra J, Lo RY, Goldman SM, Tanner CM. Environmental toxicants and Parkinson's disease: recent evidence, risks, and prevention opportunities. Lancet Neurol. 2025 Nov;24(11):976-986. doi: 10.1016/S1474-4422(25)00287-X. PMID: 41109237.

10:  Krzyzanowski B, Mullan AF, Dorsey ER, et al. Proximity to Golf Courses and Risk of Parkinson Disease. JAMA Netw Open. 2025;8(5):e259198. doi:10.1001/jamanetworkopen.2025.9198

11:  Shan L, Heusinkveld HJ, Paul KC, Hughes S, Darweesh SKL, Bloem BR, Homberg JR. Towards improved screening of toxins for Parkinson's risk. NPJ Parkinsons Dis. 2023 Dec 19;9(1):169. doi: 10.1038/s41531-023-00615-9. PMID: 38114496; PMCID: PMC10730534

12:  Paul KC, Krolewski RC, Lucumi Moreno E, Blank J, Holton KM, Ahfeldt T, Furlong M, Yu Y, Cockburn M, Thompson LK, Kreymerman A, Ricci-Blair EM, Li YJ, Patel HB, Lee RT, Bronstein J, Rubin LL, Khurana V, Ritz B. A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides. Nat Commun. 2023 May 16;14(1):2803. doi: 10.1038/s41467-023-38215-z. Erratum in: Nat Commun. 2023 Jun 23;14(1):3747. doi: 10.1038/s41467-023-39001-7. PMID: 37193692; PMCID: PMC10188516.

13:  Su D, Cui Y, He C, Yin P, Bai R, Zhu J et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021 BMJ 2025; 388 :e080952 doi:10.1136/bmj-2024-080952

14:  Bogale TA, Faustini G, Longhena F, Mitola S, Pizzi M, Bellucci A. Alpha-Synuclein in the Regulation of Brain Endothelial and Perivascular Cells: Gaps and Future Perspectives. Front Immunol. 2021 Feb 19;12:611761. doi: 10.3389/fimmu.2021.611761. PMID: 33679750; PMCID: PMC7933041.

15:  Konno T, Deutschländer A, Heckman MG, Ossi M, Vargas ER, Strongosky AJ, van Gerpen JA, Uitti RJ, Ross OA, Wszolek ZK. Comparison of clinical features among Parkinson's disease subtypes: A large retrospective study in a single center. J Neurol Sci. 2018 Mar 15;386:39-45. doi: 10.1016/j.jns.2018.01.013. Epub 2018 Jan 11. PMID: 29406964.

16:  Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression. Brain. 2017 Jul 1;140(7):1959-1976. doi: 10.1093/brain/awx118. PMID: 28549077.

17:  Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548–560. doi:10.1001/jama.2019.22360

 

 Additional References:

Gut Connection;

Dickson DW. Neuropathology of Parkinson disease. Parkinsonism Relat Disord. 2018 Jan;46 Suppl 1(Suppl 1):S30-S33. doi: 10.1016/j.parkreldis.2017.07.033. Epub 2017 Aug 1. PMID: 28780180; PMCID: PMC5718208.

Bhardwaj K, Singh AA, Kumar H. Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration-Gut Connection in Parkinson's Disease. ACS Chem Neurosci. 2024 Jul 3;15(13):2454-2469. doi: 10.1021/acschemneuro.4c00293. Epub 2024 Jun 19. PMID: 38896463.

 

IDPs:

Mukhopadhyay S. The Dynamism of Intrinsically Disordered Proteins: Binding-Induced Folding, Amyloid Formation, and Phase Separation. J Phys Chem B. 2020 Dec 24;124(51):11541-11560. doi: 10.1021/acs.jpcb.0c07598. Epub 2020 Oct 27. PMID: 33108190.

Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell. 2012 Mar 16;148(6):1188-203. doi: 10.1016/j.cell.2012.02.022. PMID: 22424229; PMCID: PMC3353745.

 

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